Clinical trial NCT04314895
Conditions: Lung Cancer, Nonsmall Cell Lung Cancer Lung Cancer, Small Cell Neoplasm of Lung
Keywords: paclitaxel
Sponsor: NanOlogy, LLC
Start date: 2021-04-14; Completion date: 2023-09-26
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates the use of NanoPac injected directly into tumors in the lung of people with lung cancer.

Detailed description:
NanoPac is very small (submicron) particles of the chemotherapy drug, paclitaxel, which is administered intravenously in a number of types of cancer. These submicron particles are injected directly into solid tumors to target cancer at the site of disease with less systemic exposure than intravenously administered chemotherapy. In this study, the submicron particle paclitaxel will be injected directly into tumors in the lungs of people with small cell or non-small cell lung cancer. All subjects in this study will receive NanoPac and will be evaluated to see if NanoPac is safe and has an effect on the tumor within the lung.

Arms: arm 1: Intratumoral injection of NanoPac 15 mg/mL at a volume of up to 20% of the total calculated tumor and lymph node volume (not to exceed 40 mL) on up to three occasions 4 weeks apart.
Interventions: intervention 1: NanoPac (sterile nanoparticulate paclitaxel) Powder for Suspension
Intervention descriptions: intervention 1: NanoPac is manufactured using a Precipitation with Compressed Antisolvent (PCA) technique that employs supercritical carbon dioxide and acetone to generate paclitaxel nanoparticles 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.

Protocol documents:
Prot_000.pdf: 
Intratumoral Injection of NanoPac in Subjects with Lung Cancer 
  
  
 
    
        Protocol NANOPAC-2020-01 
NanOlogy, LLC 
 
 
 
 
 
 
 
             
 
                  Version 4.0 
 
7 July 2021 
CONFIDENTIAL 
Page 1 of 61 
  
 
Phase 2 Trial Evaluating the Safety and Tolerability of 
Intratumoral Injections of NanoPac® with Standard of 
Care Therapy in Subjects with Lung Cancer 
 
Protocol Identifying Number: NANOPAC-2020-01 
IND Sponsor: NanOlogy, LLC 
IND #: 147012 
Version Number: 4.0 
Date: 7 July 2021 
 
 
 
 
 
 


Intratumoral Injection of NanoPac in Subjects with Lung Cancer 
  
  
 
    
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                  Version 4.0 
 
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Table of Contents 
Table of Contents....................................................................................................................................................... 2 
LIST OF ABBREVIATIONS ................................................................................................................................................ 5 
SPONSOR SIGNATURE PAGE .......................................................................................................................................... 7 
STATEMENT OF COMPLIANCE ....................................................................................................................................... 8 
PROTOCOL SUMMARY ................................................................................................................................................... 9 
1 
KEY ROLES ....................................................................................................................................................... 14 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............................................... 15 
2.1 
Background Information ...................................................................................................................... 15 
2.2 
Rationale .............................................................................................................................................. 19 
2.3 
Potential Risks and Benefits ................................................................................................................. 21 
2.3.1 
Known Potential Risks ....................................................................................................... 21 
2.3.2 
Known Potential Benefits ................................................................................................. 21 
3 
OBJECTIVES AND PURPOSE ............................................................................................................................. 21 
4 
STUDY DESIGN AND ENDPOINTS ..................................................................................................................... 22 
4.1 
Description of the Study Design ........................................................................................................... 22 
4.2 
Endpoints .............................................................................................................................................. 23 
4.2.1 
Primary Endpoint .............................................................................................................. 23 
4.2.2 
Secondary Endpoints ........................................................................................................ 24 
4.2.3 
Exploratory Endpoints ...................................................................................................... 24 
5 
STUDY ENROLLMENT AND WITHDRAWAL ...................................................................................................... 24 
5.1 
Participant Inclusion Criteria ................................................................................................................ 24 
5.2 
Participant Exclusion Criteria ............................................................................................................... 25 
5.3 
Strategies for Recruitment and Retention ........................................................................................... 25 
5.4 
Participant Withdrawal or Termination ............................................................................................... 25 
5.4.1 
Reasons for Withdrawal or Termination .......................................................................... 25 
5.4.2 
Handling of Participant Withdrawals or Termination ....................................................... 26 
5.5 
Premature Termination or Suspension of Study .................................................................................. 26 
6 
STUDY AGENT .................................................................................................................................................. 27 
6.1 
Study Agent(s) and Control Description ............................................................................................... 27 
6.1.1 
Acquisition ........................................................................................................................ 27 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ......................................................... 27 
6.1.3 
Product Storage and Stability ........................................................................................... 28 
6.1.4 
Preparation ....................................................................................................................... 28 
6.1.5 
Dosing and Administration ............................................................................................... 28 
6.1.6 
Route of Administration ................................................................................................... 29 
6.1.7 
Dose Adjustments/Modifications/Delays ......................................................................... 29 
6.1.8 
Duration of Therapy .......................................................................................................... 30 
6.1.9 
Tracking of Dose ............................................................................................................... 30 
6.1.10 
Device Specific Considerations ......................................................................................... 30 
6.2 
Study Agent Accountability Procedures ............................................................................................... 30 
7 
STUDY PROCEDURES AND SCHEDULE ............................................................................................................. 30 
7.1 
Study Procedures/Evaluations ............................................................................................................. 30 
7.1.1 
Study Specific Procedures ................................................................................................. 30 
7.1.2 
Standard of Care Study Procedures .................................................................................. 31 
7.2 
Laboratory Procedures/Evaluations ..................................................................................................... 32 
7.2.1 
Clinical Laboratory Evaluations ......................................................................................... 32 
7.2.2 
Other Assays or Procedures .............................................................................................. 32 
7.2.3 
Specimen Preparation, Handling, and Storage ................................................................. 33 
7.2.4 
Specimen Shipment .......................................................................................................... 33 
7.3 
Study Schedule ..................................................................................................................................... 33 
7.3.1 
Screening 33 


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7.3.2 
Days of NanoPac Injection – Day 1, week 4, week 8 ........................................................ 34 
7.3.3 
Follow-Up Visits ................................................................................................................ 35 
7.3.4 
PRIMARY ENDPOINT Study Visit (week 24, approximately 6 months) ............................. 36 
7.3.5 
Follow up visit week 38 and END OF STUDY WEEK 52 ...................................................... 36 
7.3.6 
Early Termination Visit ...................................................................................................... 37 
7.3.6 
Unscheduled Visits ............................................................................................................ 37 
7.3.7 
Schedule of Events Table .................................................................................................. 38 
7.4 
Justification for Sensitive Procedures .................................................................................................. 40 
7.5 
Concomitant Medications, Treatments, and Procedures .................................................................... 40 
7.6 
Precautionary Medications, Treatments, and Procedures ................................................................... 40 
7.7 
Prohibited Medications, Treatments, and Procedures ........................................................................ 40 
7.8 
Prophylactic Medications, Treatments, and Procedures ..................................................................... 40 
7.9 
Rescue Medications, Treatments, and Procedures .............................................................................. 41 
7.10 
Participant Access to Study Agent At Study Closure ............................................................................ 41 
8 
ASSESSMENT OF SAFETY ................................................................................................................................. 41 
8.1 
Specification of Safety Parameters ...................................................................................................... 41 
8.1.1 
Definition of Adverse Events (AE) ..................................................................................... 42 
8.1.2 
Definition of Serious Adverse Events (SAE) ...................................................................... 42 
8.1.3 
Definition of Unanticipated Problems (UP) ...................................................................... 43 
8.2 
Classification of an Adverse Event ........................................................................................................ 43 
8.2.1 
Severity of Event ............................................................................................................... 43 
8.2.2 
Relationship to Study Agent ............................................................................................. 43 
8.2.3 
Expectedness .................................................................................................................... 44 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up ...................................................... 44 
8.4 
Reporting Procedures ........................................................................................................................... 45 
8.4.1 
Adverse Event Reporting .................................................................................................. 45 
8.4.2 
Serious Adverse Event Reporting...................................................................................... 45 
8.4.3 
Unanticipated Problem Reporting .................................................................................... 46 
8.4.4 
Events of Special Interest.................................................................................................. 46 
8.4.5 
Reporting of Pregnancy .................................................................................................... 46 
8.5 
Study Halting Rules ............................................................................................................................... 46 
8.6 
Safety Oversight ................................................................................................................................... 47 
9 
CLINICAL MONITORING ................................................................................................................................... 47 
10 
STATISTICAL CONSIDERATIONS ....................................................................................................................... 48 
10.1 
Statistical and Analytical Plans ............................................................................................................. 48 
10.2 
Statistical Hypotheses .......................................................................................................................... 48 
10.3 
Analysis Datasets .................................................................................................................................. 48 
10.3.1 
Missing Data ..................................................................................................................... 48 
10.4 
Description of Statistical Methods ....................................................................................................... 48 
10.4.1 
General Approach ............................................................................................................. 48 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) .................................................................... 49 
10.4.3 
Analysis of the Secondary Endpoint(s) ............................................................................. 49 
10.4.4 
Safety Analyses ................................................................................................................. 49 
10.4.5 
Adherence and Retention Analyses .................................................................................. 50 
10.4.6  
Baseline Descriptive Statistics .......................................................................................... 50 
10.4.7 
Planned Interim Analyses ................................................................................................. 50 
10.4.8 
Additional Sub-Group Analyses ........................................................................................ 51 
10.4.9 
Multiple Comparison/Multiplicity .................................................................................... 51 
10.4.10 
Tabulation of Individual Response Data ........................................................................... 51 
10.4.11 
Exploratory Analyses ........................................................................................................ 51 
10.4.12 
Concomitant Medication .................................................................................................. 51 
10.5 
Sample Size ........................................................................................................................................... 52 
10.6 
Measures to Minimize Bias .................................................................................................................. 52 


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10.6.1 
Enrollment/ Randomization/ Masking Procedures .......................................................... 52 
10.6.2 
Evaluation of Success of Blinding ...................................................................................... 52 
10.6.3 
Breaking the Study Blind/Participant Code ...................................................................... 52 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ........................................................... 52 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................................................. 53 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................................... 53 
13.1 
Ethical Standard ................................................................................................................................... 53 
13.2 
Institutional Review Board ................................................................................................................... 54 
13.3 
Informed Consent Process ................................................................................................................... 54 
13.3.1 
Consent/Assent and Other Informational Documents Provided to Participants ............. 54 
13.3.2 
Consent Procedures and Documentation ......................................................................... 54 
13.4 
Participant and Data Confidentiality .................................................................................................... 55 
13.4.1 
Research Use of Stored Human Samples, Specimens or Data .......................................... 55 
13.5 
Future Use of Stored Specimens .......................................................................................................... 56 
14 
DATA HANDLING AND RECORD KEEPING ........................................................................................................ 56 
14.1 
Data Collection and Management Responsibilities .............................................................................. 56 
14.2 
Study Records Retention ...................................................................................................................... 57 
14.3 
Protocol Deviations .............................................................................................................................. 57 
14.4 
Publication and Data Sharing Policy ..................................................................................................... 58 
15 
STUDY ADMINISTRATION ................................................................................................................................ 58 
15.1 
Study Leadership .................................................................................................................................. 58 
16 
CONFLICT OF INTEREST POLICY ....................................................................................................................... 58 
17  
LIABILITY AND INSURANCE .............................................................................................................................. 59 
18  
LITERATURE REFERENCES ................................................................................................................................ 60 
APPENDIX A: ECOG Performance Scale ....................................................................................................................... 61 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALCOA-C 
Attributable, Legible, Contemporaneous, Original, and Accurate - Complete 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
ASP 
Alkaline Phosphatase 
BUN 
Blood Urea Nitrogen 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
Central Nervous System 
CO2 
Carbon Dioxide 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-Limiting Toxicity 
EBUS-TBNI 
Endobronchial ultrasound-guided transbronchial needle injection 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture System 
eCRF 
Electronic Case Report Form 
EUS-FNI 
Endoscopic ultrasound-guided fine needle injection 
FCM 
Flow Cytometric 
FDA 
The U.S. Food and Drug Administration 
FNA 
Fine Needle Aspiration 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyltransferase 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
CT Scan 
Computed Tomography Scan 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IFU 
Instructions for Use 
IHC 
Immunohistochemical 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IP 
Intraperitoneal 
IRB 
Institutional Review Board 
ITP 
Intraprostatic 
ITU 
Intratumoral  
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
LN 
Lymph Node 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 


Intratumoral Injection of NanoPac in Subjects with Lung Cancer 
  
  
 
    
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MedDRA 
Medical Dictionary for Regulatory Activities  
NCI 
National Cancer Institute 
NDA 
New Drug Application (Marketing Application) 
PCA 
Precipitation with Compressed Antisolvents 
PD 
Pharmacodynamic 
PFS 
Progression-free Survival 
pH 
Hydrogen Ion Concentration 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PRO 
Patient Reported Outcomes 
PT 
Prothrombin Time 
PTT 
Activated Partial Thromboplastin Time 
QOL 
Quality of Life 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDLC 
Systems Development Life Cycle 
SOC 
Standard of Care 
SRC 
Safety Review Committee 
TEAE 
Treatment-emergent Adverse Event 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
VAS 
Visual Analog Score 
WBC 
White Blood Cell 
 
 
 
 


lntratumoral lnjection of NanoPac in Subjects with Lung Cancer
NanOlogy, LLC
Protocol NANOPAC-2020-01
Version 4.0
SPONSOR SIGNATURE PAGE
ProtocolTitle:
Phase 2 Trial Evaluating the Safety and Tolerability of lntratumoral
lnjections of NanoPac with Standard of Care therapy in Subjects with
Lung Cancer.
ProtocolNumber:
NANOPAC-2020-01
Version Number:
Date:
7 July 2021:
IND Number:
L470t2
Study Agent:
NanoPac@ (sterile nanopa rticulate paclitaxel) Powder for Suspension
Sponsor:
NanOlogy, LLC
231 Bonetti Dr., Suite 240
San Luis Obispo, CA 93401-7310
805-595-L300
The Sponsor for IND L47OL2, NanOlogy, LLC, has transferred responsibility for all obligations set forth in
21 CFR Part 3L2 to US Biotest, lnc., with regard to the IND; in accordance with 21 CFR Part 312, US
Biotest, lnc., shall be considered the sponsor with regard to all activities related to the lND.
SIGNATURE
4.0
Sponso/s Representative - Name and Title:
Gere diZerega, MD
President & CEO, US Biotest, lnc.
6zrplDn non
6eredizereB. tJur 7. 2o!(lo:,0 PDr)
July 7,202t
Signature of Sponsor's Representative
Date
7 July2O2l
CONFIDENTIAL
Page 7 of 61


Intratumoral Injection of NanoPac in Subjects with Lung Cancer 
  
  
 
    
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Page 8 of 61 
STATEMENT OF COMPLIANCE 
 
I have read the attached protocol number NANOPAC-2020-01 entitled, Phase 2 Trial Evaluating the 
Safety and Tolerability of Intratumoral Injections of NanoPac with Standard of Care Therapy in Subjects 
with Lung Cancer, Version 4.0 dated 7 July 2021 and agree to comply with the contents of this 
document. 
I agree to comply with applicable FDA regulations and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, 
and 312. 
This document is a confidential communication of US Biotest, Inc. The recipient agrees that no 
unpublished information contained herein will be published or disclosed without prior written 
permission of US Biotest. However, this document may be disclosed to appropriate institutional review 
boards, ethics review committees, or authorized representatives of the Investigator or of boards of 
health under the condition that they are requested to respect the confidentiality of the document. 
The signature of the Principal Investigator below constitutes his/her agreement. 
 
 
__________________________________________ 
__________________________ 
Signature of Principal Investigator 
 
 
Date 
 
 
 
__________________________________________ 
Printed Name of Principal Investigator 
 
 


Intratumoral Injection of NanoPac in Subjects with Lung Cancer 
  
  
 
    
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PROTOCOL SUMMARY 
 
Title: 
Phase 2 Trial Evaluating the Safety and Tolerability of Intratumoral Injections of 
NanoPac® with Standard of Care therapy in Subjects with Lung Cancer 
 
Précis: 
In this open-label trial, 18 subjects with lung cancer will receive intratumoral (ITU) 
NanoPac® (sterile nanoparticulate paclitaxel) Powder for Suspension via 
endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI).  
 
Eligible subjects include primary or recurrent non-resectable non-small cell lung 
cancer (NSCLC) or small cell lung cancer (SCLC), with primary or recurrent 
measurable disease limited to the tracheal, hilar, mediastinal, and peribronchial 
structures (lung tumors and lymph nodes) accessible through EBUS-TBNI, have a life 
expectancy of at least 6 months, do not have cerebral metastases, ECOG ≤ 2, severe 
infection and other metabolic disorders, prior sensitivity/anaphylaxis to paclitaxel, or 
any other clinically significant comorbid disease that may limit the ability of the 
subject to participate in the study (e.g. significant cardiorespiratory disease that 
potentially limits the ability to undergo the injection procedure). 
 
Subjects may receive concomitant standard of care intravenous (IV) chemotherapy, 
radiation therapy, and/or targeted therapy as required for their care.   
 
Subjects will be administered NanoPac on three occasions, at a 15 mg/mL 
concentration 4 weeks apart, up to 20% of the total calculated tumor and lymph 
node volume to allow for up to a maximum volume of 40 mL per bronchoscopic 
procedure (i.e. the total tumor volume that can be treated is 200 mL). Up to two 
pulmonary parenchymal lesions will be injected, along with the metastatic lymph 
nodes selected by the Investigator based on CT findings at baseline and tumor 
accessibility through EBUS-TBNI. The volume of NanoPac to be delivered at all three 
injection procedures will be estimated based on the tumor and lymph node volume 
calculation from CT imaging obtained at baseline. At each injection visit, tumor size/s 
will also be measured using EBUS, and the tumor/s and node/nodal sizes recorded 
for comparison only. The volume of NanoPac injected, total and/or lesional, will at 
no time be increased beyond the maximum as calculated by the baseline CT 
measurement(s). Delivery of NanoPac to the lesion may be via multiple 
injections/sticks to maximize the dispersal of NanoPac throughout each individual 
lesion. 
 
NanoPac injections will be planned according to the following schedule: 
 
• 
Day 1 – first injection, Week 4 – second injection, Week 8 – third injection. 
o Follow-up visits will occur 1 and 2 weeks following each injection; 
o Additional follow-up visits will occur at Weeks 12, 18, 24, and 38 (9 
months following first injection); 
o End of Study visit will occur at Week 52 (12 months following first 
injection). 
 


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All safety parameters will be evaluated alongside the results of the CT scans by the 
Medical Monitor at regular intervals (monthly) throughout the study period. All 
imaging will be made available to the Sponsor. Any personal information that could 
identify the subject will be removed before images are shared with the Sponsor. 
Data will be reviewed for subjects independently and as a group during this review. 
Discussion with the Investigator and the Sponsor Medical Director may be 
required/requested at any time by the Medical Monitor. In addition, the first three 
subjects will be enrolled singly and sequentially, and a safety review will be 
performed by the Safety Review Committee (SRC) (by teleconference) after the first 
subject has undergone the 2-week follow-up visit after their first administration of 
NanoPac to confirm that the second subject may proceed to injection. This safety 
review process will be repeated for the second and third subjects in a sequential 
manner prior to opening general enrollment to the study. The SRC will also perform 
a safety review after each of the first three subjects has undergone the 2-week 
follow-up visit after their second administration of NanoPac. The SRC will include the 
Sponsor Medical Director, the Principal Investigator, Medical Monitor, and an 
independent therapeutic area specialist.  
 
Blood samples will be obtained from subjects for pharmacokinetic (PK) evaluation of 
paclitaxel in the systemic circulation and at set time points for flow cytometric (FCM) 
evaluation of immune markers. Tissue samples (biopsies) may be obtained at each 
injection prior to the administration of NanoPac to evaluate the presence of 
paclitaxel in the tissue and for evaluation via immunohistochemical (IHC) staining for 
immune markers. 
 
All subjects will undergo CT scans within 4 weeks prior to start of treatment, prior to 
each injection at Weeks 4 and 8, and again at Weeks 12, 18, 24,  38 and 52 (End of 
Study Visit). CT scans will be used to provide preliminary signs of the effect of 
NanoPac on the lesion(s) and nodes. The baseline redacted CT scan will be 
forwarded to the Medical Monitor for review/approval with the completed pre-
injection form prior to first injection for all subjects.  All imaging will be collected for 
the subject’s record and identifiers removed before images are shared with the 
Sponsor.  At the second and third injections the same volume/dose of NanoPac will 
be administered to each lesion as was administered at the first bronchoscopic 
procedure.  
 
Subjects will be followed for a total of a year after the first NanoPac injection; 
assessments during this time will be primarily for safety (laboratory values, adverse 
events, concomitant medications, etc.) during the first 6 months of the study, and 
information will be obtained to evaluate progression-free survival (PFS) using the 
RECIST 1.1 criteria, and radiological changes using the CT scans.  The assessments at 
Week 38 and Week 52 will provide additional information on PFS and overall survival 
(OS).  Subjects will also complete a quality of life (QOL) questionnaire (EQ-5D) prior 
to first injection of NanoPac, and throughout the study until the End of the Study at 
Week 52. Subjects will be grouped for review at study completion based on the 
number of treatments (bronchoscopic procedures) they received. 
 
Objectives: 
Primary objective: 


Intratumoral Injection of NanoPac in Subjects with Lung Cancer 
  
  
 
    
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• 
To evaluate the safety and tolerability of NanoPac injected directly into lung 
cancer lesions and metastatic lymph nodes by endobronchial ultrasound-
guided injection on up to three occasions, each occasion 4 weeks apart. 
 
 
Secondary objectives:  
• 
PK evaluation - paclitaxel in the systemic circulation and in tissue samples; 
• 
To evaluate effect on PFS and OS in this population; 
• 
To assess changes in the treated lesion (and lymph nodes) via CT scan 
imaging.  
 
Endpoints: 
Primary endpoint:  
• 
Safety and tolerability as demonstrated by adverse events (AEs), changes in 
laboratory assessments, physical examination findings and vital signs. 
 
 
Secondary endpoints: 
• 
Blood samples will be evaluated for paclitaxel levels at all clinic visits; tissue 
obtained at the second and third injection timepoints will be compared 
against baseline paclitaxel levels obtained from a pre-NanoPac sample taken 
prior to the first injection; 
• 
PFS defined as change in tumor size classified using RECIST 1.1, metastatic 
disease, and death; OS as determined by survival time following first 
NanoPac injection; 
• 
Assessment of tumor response (dimensions, volume) as determined by CT 
scan imaging, measured at baseline and Weeks 12, 24, 38 and 52; 
o Any changes in characteristics of lesion/nodes as determined via CT 
scan. 
 
Exploratory/Tertiary endpoints: 
• 
Changes in Eastern Cooperative Oncology Group (ECOG) Performance 
Status; 
• 
Changes in pain (as measured by the visual analog scale [VAS]) in the first 6 
months of the study; 
• 
Changes in QOL as measured by the validated EQ-5D QOL instrument; 
• 
Assess immune markers in the blood via FCM, and in the tissues via IHC in 
the first 6 months of the study.  
 
Population: 
Eighteen subjects with primary or recurrent non-resectable NSCLC or SCLC lung 
cancer, with primary or recurrent measurable disease limited to the tracheal, hilar, 
mediastinal, and peribronchial structures (lung tumors and lymph nodes) accessible 
through EBUS-TBNI. 
 
Phase: 
Phase 2 
 
Number of 
Sites enrolling 
participants: 
 
Up to five (5) 


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Description of 
Study Agent: 
NanoPac® (sterile nanoparticulate paclitaxel) Powder for Suspension (“NanoPac”) at 
concentration of 15 mg/mL administered into the tumor within the lung via EUS-
TBNI. 
 
Study 
Duration: 
The study duration is estimated to be up to 36 months. 
 
Participant 
Duration: 
The study duration is estimated to be up to 13 months for each subject – Screening 
may occur up to one month prior to first injection. 


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STUDY SCHEDULE 
 
  
Screening6 
Day 1 
Week 
1 
  
Week 4 
  
  
Week 8 
  
  
  
  
Week 
24 
Week 
38 
Week 
52 
NanoPac 
Week 
2 
NanoPac 
Week 
5 
Week 
6 
NanoPac 
Week 
9 
Week 
10 
Week 
12 
Week 
18 
(6 
months) 
(9 
months) 
(12 
months) 
Informed 
Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History1 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Exam 
X 
X 
  
  
X 
  
  
X 
  
  
  
  
X 
  
  
Pain 
Assessment4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
QOL 
Questionnaire 
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
X 
X 
Vital Signs 
 X 
 X 
X 
X 
X  
X 
X 
 X 
X 
X 
X 
X 
X  
X 
X 
ECOG2 
 X 
 X 
  
  
 X 
  
  
 X 
  
  
X 
X 
 X 
X 
X 
Clinical 
Laboratory 
Tests8,9 
X 
X 
  
X 
X 
  
X 
X 
  
X 
X 
X 
X 
 
 
PK Samples 
(blood)3 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood FCM 
analysis 
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X  
 
 
Tissue (biopsy) 
for IHC and 
paclitaxel 
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
 
 
Imaging (CT 
Scans)5 
X 
  
  
  
X 
  
  
X 
  
  
X 
X 
X 
X 
X 
NanoPac 
Procedure 
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
Pharmacy  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
Concomitant 
Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7 
X7 
Adverse Events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
 
1 
History includes all events before initiation of NanoPac treatment. 
2 
ECOG Performance Status Scale attached as Appendix A. 
3 
PK Samples on Day 1, Week 4, and Week 8 will be drawn prior to injection and at 1, 2, and 4 hours post-dose. PK samples 
will also be obtained at each study visit thereafter. PK samples within the first 4 hours on Day 1 will allow for a 10-minute 
window around the samples.  
4 
Pain will be assessed with the visual analog scale. 
5 
Imaging with CT scan will occur during the screening period, prior to each NanoPac administration, and at Weeks 12, 18, 24, 
38 and 52. Should the subject withdraw from the study at any time, a CT 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 standard of care and all 
resulting images will be collected for the subject’s record.  
6       Screening will occur up to four weeks prior to injection.  
7       All concomitant medications will be captured to Week 24.  Only SOC lung cancer therapy will be captured at visit Weeks 38 
and 52. 
8        Urine pregnancy test for women of child-bearing potential at screening, Week 12 and Week 24. 
9       Clinical laboratory tests include hematology, chemistry, urinalysis and at screening includes serology (Hepatitis A, Hepatitis, 
B, HIV). 
 
 


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1 
KEY ROLES 
 
Medical Director 
Gere diZerega, MD 
President & CEO, US Biotest, Inc. 
Professor, University of Southern California Keck School of Medicine 
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-630-2800 
gere.dizerega@usbiotest.com 
Study Director 
Shelagh Verco, PhD 
US Biotest, Inc.  
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-704-1179 
shelagh.verco@usbiotest.com 
Medical Monitor 
Antony Verco, MD 
US Biotest, Inc.  
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-235-9193 
tony.verco@usbiotest.com 
Laboratory – PK Samples 
Covance Madison Laboratories Bioanalytical (BA) Group  
3301 Kinsman Blvd, Madison, WI 53704 
608-442-8200 
 
Central Laboratory – Immunohistochemistry on Biopsies  
NeoGenomics Laboratories, Inc.  
Attn: Pharma Services Department  
31 Columbia  
Aliso Viejo, CA 92656  
Phone: 949-445-7300 x7103  
 
Central Laboratory – FCM evaluation on whole blood  
NeoGenomics Laboratories, Inc.  
Attn: Pharma Services Department  
31 Columbia  
Aliso Viejo, CA 92656  
Phone: 949-445-7300 x7103  
 


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2  INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
2.1 
BACKGROUND INFORMATION  
The Sponsor for IND 147012, NanOlogy, LLC, has transferred responsibility for all obligations set forth in 
21 CFR Part 312 to US Biotest, Inc., with regard to the IND. In accordance with 21 CFR Part 312, US 
Biotest, Inc., shall be considered the sponsor with regard to all activities related to the IND. Therefore, 
references to “Sponsor” hereafter in this protocol refer to US Biotest, Inc.  
Name and description of study agent: 
NanOlogy, LLC (NanOlogy) has produced a formulation of nanoparticulate paclitaxel, identified as 
NanoPac® (sterile nanoparticulate paclitaxel) Powder for Suspension (NanoPac), which is the subject of 
this protocol. NanoPac, previously called Nanotax®, is manufactured using a Precipitation with 
Compressed Antisolvent (PCA) technique that employs supercritical carbon dioxide and acetone to 
generate paclitaxel nanoparticles within a well-characterized particle-size distribution. Following PCA, 
NanoPac is filled into a clear 60mL Type 1, USP, clear-glass vial (306 mg/vial) as a powder fill of 
nanoparticulate paclitaxel, closed with a bromobutyl rubber stopper and aluminum crimp seal, and 
sterilized by gamma irradiation. Prior to administration at the hospital/clinic, NanoPac will be 
reconstituted with 1% Polysorbate 80, NF in 0.9% Sodium Chloride for Injection, USP, to form a 
suspension. The suspension will be further diluted with 0.9% Sodium Chloride for Injection, USP to 
achieve the final clinical formulation. This reconstitution and dilution will occur at the clinical site’s 
Pharmacy. 
Nonclinical Summary: 
Nonclinical studies of intratumoral (ITU) injection of NanoPac in animal models of lung cancer have not 
been performed. However, NanoPac has demonstrated preliminary safety and efficacy when injected 
ITU in animals with solid tumors and when administered as an inhalation therapy in animal models of 
lung cancer. Preclinical data is presented in the NanoPac Investigator’s Brochure.  
Two in vivo nonclinical pharmacology studies were conducted to determine the effects of ITU delivery of 
nanoparticulate paclitaxel in a nude mouse xenograft model. Animals treated with NanoPac 
demonstrated significant reduction in tumor size (p < 0.01 for all comparisons) and survival benefit (p < 
0.01 for all comparisons) compared to vehicle-treated animals. NanoPac reduced mean tumor volume 
by 74.1% by Day 22 compared to vehicle; body weights for all groups remained stable or increased 
throughout the treatment phase. 
A GLP-compliant study (Study Number P-TR-06-2018) evaluated and characterized the toxicity and 
toxicokinetics (TK) of NanoPac following a single intraprostatic (ITP) administration into the prostate in 
rats. There were no test article-related findings in mortality, clinical or ophthalmological observations, 
organ or body weights, food consumption, hematology, coagulation or clinical chemistry. The death of 1 
out of 20 animals/dose group at 0 (control) and 2.9 mg/kg NanoPac were considered procedure-related, 
were likely due to a combination of local trauma of injection compounded by the local irritation of 


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paclitaxel in and around the injection site. At the terminal interval on Day 4, findings of necrosis with 
mixed inflammation and fibrin deposition were noted in the prostate, with mineralization (kidneys), 
mixed inflammation and fibrin deposition (urinary bladder, seminal vesicles and iliac lymph nodes) 
noted in the adjacent tissues. At the recovery interval on Day 28 (± 1), similar findings were observed, 
with partial/ongoing to complete resolution. 
The toxicity of NanoPac was evaluated following a single ITP dose in rats. In this non-GLP study (Study 
Number P-TR-04-2016), there were no NanoPac-related findings in the following parameters evaluated: 
mortality, clinical observations, body weights, food consumption, coagulation, clinical chemistry, or 
urinalysis. The death of 1 out of 10 animals/dose group at 8 and 16 mg/kg NanoPac on Day 3 was 
considered treatment-related but not dose-related. Clinical signs preceding death were limited to 
decreased activity. Microscopic examination revealed the cause of death was due to urinary obstruction 
which appeared to have been caused by seminal plugs in the prostatic urethra with secondary backflow 
in the bladder, ureters, and kidneys. These deaths were considered due to a combination of the local 
trauma of injection compounded by the local irritation of paclitaxel at and around the injection site. 
NanoPac administered by other routes of administration include the intraperitoneal and inhaled routes. 
Intraperitoneal (IP) administration of NanoPac has demonstrated less toxicity than IP Taxol, and 
increased survival and tumor load reduction with or without surgical debulking. GLP and non-GLP single 
and multiple dose toxicity studies in rats and dogs, and an in vivo proof-of-concept study of NanoPac in a 
mouse xenograft study were conducted via the inhaled route of administration. These studies 
demonstrated preliminary efficacy with toxicity as expected for the route of administration viz. minimal 
systemic effects due to lack of absorption across the lung parenchyma, and dose-responsive airway 
epithelial changes secondary to cytotoxicity induced by NanoPac (inflammation, necrosis, fibrosis, 
pneumonitis). 
Clinical Summary: 
NanoPac has not previously been administered to the human lung via EBUS-TBNI. Two clinical studies 
with NanoPac have been completed – one Phase 2a study of ITP injection of NanoPac in locally-
advanced prostate cancer and one Phase 1 study of IP NanoPac in patients with peritoneal malignancies. 
Additional data from these clinical trials is presented in the NanoPac Investigator’s Brochure.  
Phase 2a Study in Prostate Cancer 
In this study of NanoPac focal therapy of prostate cancer (NANOPAC-2016-02; NCT03077659), ITP 
NanoPac was injected in ascending concentrations of 6, 10, and 15 mg/mL in an injection volume of 20% 
of the lobe of the prostate containing the dominant lesion. Subjects were followed for 4 weeks for 
safety and tolerability prior to prostatectomy. The primary objective of the study was to evaluate the 
safety and tolerability of NanoPac. Sixteen subjects were enrolled and received study agent according to 
the protocol. The majority of subjects experienced treatment emergent adverse events (TEAEs) as 
expected, but with minimal frequency, severity, and relation to NanoPac. The most frequent TEAEs 
occurred in the system organ class of gastrointestinal disorders, most of which were in the 6 mg/mL  
cohort. There was no obvious dose-response relationship with respect to the frequencies of the TEAEs. 


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Compared to Taxol, no dose-limiting toxicities (DLTs) or toxicities typically attributable to paclitaxel such 
as neutropenia, thrombocytopenia, peripheral neuropathy, and hypersensitivity reactions such as 
angioedema and urticaria were reported. There were no serious adverse events (SAEs), deaths, or 
discontinuations from the study due to adverse events (AEs).  
 
Pharmacokinetic (PK)/pharmacodynamic (PD) modeling of Taxol-induced neutropenia suggests toxicity 
is related to the duration and extent of systemic exposure to paclitaxel which correlates with a threshold 
plasma paclitaxel concentration of ≥ 42.7 ng/mL. In contrast, plasma paclitaxel concentrations observed 
after administration of NanoPac in clinical study NANOPAC-2016-02 had Cmax values of 19 to 20 ng/mL 
recorded at the earliest sample (the 1-hour timepoint). In addition, and by comparison, a standard 
intravenous (IV) dose of paclitaxel of 175 mg/m2 BSA administered over 3 hours resulted in a Cmax of 
3,650 ng/ml (Paclitaxel Drug Label Information – Teva), about 192x higher than the mean NanoPac 
concentration achieved in the 15 mg/mL cohort at 1 hour after injection. In alignment with this, from a 
toxicity and safety perspective, ITP injection of NanoPac appears to have a better risk profile compared 
to IV Taxol administration. The original hypothesis of NANOPAC-2016-02, that direct injection of 
NanoPac into the prostate would result in limited systemic exposure to paclitaxel and should therefore 
result in only low-grade and transitory AEs is therefore supported by the safety findings in the study. 
Due to the small size of the study and the natural slow rate of progression of prostate cancer, the 
majority of the individual outcomes showed no changes or variable results across the three 
concentrations of NanoPac over 4 weeks of exposure to NanoPac. The mean volume of the prostate 
increased between the time of injection and prostatectomy, likely due to the local inflammatory 
reaction generated by NanoPac. Reflecting this, the sexual health as measured by the Sexual Health 
Inventory for Men (SHIM) deteriorated over the course of participation, which can be explained by the 
increased local pressure effects created by the increased prostate volume. Notably, the mean total 
Gleason score remained stable in the 6 mg/mL and 10 mg/mL cohorts, and improved in the 15 mg/mL 
cohort, implying a possible dose-response relationship. Preliminary efficacy was demonstrated by (1) 13 
of 16 subjects had stable or improved Gleason scores (all in the 15 mg/mL cohort); (2) 11 of 16 subjects 
had stable or improved proportions of cancer lesion tissue defined as adenocarcinoma (6 of 11 subjects 
showed reductions in proportion of tissue identified as adenocarcinoma while 5 showed no change); 
and (3) 11 of 16 subjects had stable or improved levels of invasion by the cancerous tissue (4 of the 11 
subjects showed less invasion into the surrounding tissues, while 7 subjects showed stable disease). 
Overall, the primary objective of the study was achieved, i.e. preliminary evidence indicates that direct 
injection of NanoPac into the prostate appeared safe and tolerable.  
Phase 1 Study in Peritoneal Malignancies 
A Phase 1 study of intraperitoneal (IP) NanoPac in subjects with peritoneal malignancies, HSC#11140 
(NCT00666991) was completed. The results of this study were published by Williamson 2015 in the 
journal Cancer Chemotherapy and Pharmacology. 
 


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HSC#11140 was a dose-escalating study evaluating IP administered Nanotax (the same drug as NanoPac, 
but under a different name) at doses of 50-275 mg/m2 given every 28 days until disease progression or 
unacceptable toxicity occurred. Twenty-two patients were enrolled in the study. IP administration of 
NanoPac did not lead to increases in systemic toxicity over that typically associated with IV paclitaxel. No 
Grade 2 or higher neutropenia and/or Grade 3 or higher neurologic toxicities were reported. Grade 3 
thrombocytopenia, considered unlikely to be related to study agent, occurred in one patient. The 
peritoneal concentration-time profile of paclitaxel rose during the two days after dosing to peritoneal 
fluid concentrations 450-2900 times greater than peak plasma drug concentrations and remained 
elevated through the entire dose cycle. Best response assessments were made in 16 of the 21 subjects. 
Four subjects were assessed as stable or had no response and 12 subjects had progressive disease. Five 
of 21 patients with advanced cancers survived longer than 400 days after initiation of IP NanoPac 
treatment.  
Phase 2 Study in Ovarian Cancer 
Clinical trial NANOPAC-2016-01 entitled, “Phase II Study of Four Dose Levels of Intraperitoneal 
NanoPac® plus IV Carboplatin and Paclitaxel in Patients with Epithelial Ovarian Cancer Undergoing 
Cytoreductive Surgery,” was a phase 2, open-label, dose-finding trial, designed to evaluate preliminary 
safety and efficacy of four concentrations of IP NanoPac plus six cycles of IV carboplatin and IV paclitaxel 
in patients with platinum-sensitive recurrent stage III epithelial ovarian cancer. Subjects had NanoPac 
instilled directly into the peritoneum just prior to surgical cytoreductive close. A total of 10 subjects 
were enrolled into the study, seven into the 100 mg/m2 cohort and three into the 200 mg/m2 cohort.  At 
least one TEAE was reported in 10 of 10 subjects. A total of 108 TEAEs were reported for both NanoPac 
concentration cohorts (80 TEAEs in 100 mg/m2; 28 TEAEs in 200 mg/m2). Although statistical 
comparisons were not performed, there was no apparent association of the number of TEAEs with the 
dose administered. There were no TEAEs which led to subject discontinuation, however one TEAE 
occurred in each concentration cohort which lead to a fatal outcome; both were attributed to 
progression of disease. The majority of TEAEs occurred in the gastrointestinal System Organ Class (SOC) 
in the 100 mg/m2 and 200 mg/m2 dose groups and were mostly nausea and vomiting in both groups. 
Fourteen TEAEs were graded as severe or worse; 10 occurred in the 100 mg/m2 dose group, and four 
occurred in the 200 mg/m2 dose group. Thirty-seven TEAEs were considered possibly related to IP 
NanoPac, 27 events occurred in five subjects in the 100 mg/m2 dose group, and 10 events occurred in 
two subjects in the 200 mg/m2 dose group. Overall, a 66% progression free survival (PFS) occurred at 12 
months post-IP NanoPac, with further improvement noted at 18 months after treatment, supported by 
sustained reduction in CA-125 and lack of additional cancer-related symptoms six months or more after 
treatment. 
Study in Pancreatic Mucinous Cystic Neoplasms 
Completed clinical trial NANOPAC-2017-01 entitled “A Trial Evaluating Escalating Doses and the Safety of 
Intracystic Injection of NanoPac in Subjects with Mucinous Cystic Pancreatic Neoplasms,” was an open-
label, dose escalating trial injecting NanoPac into a single mucinous cystic pancreatic neoplasm 
(diameter ≥ 1.5 cm and ≤ 4 cm) via endoscopic ultrasound-guided fine needle injection (EUS-FNI). 
Subjects were followed for cyst response to therapy as shown by imaging, and concentration of 


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paclitaxel in the systemic circulation post-injection. In total, 20 subjects were enrolled into the study; 19 
received NanoPac. Overall, 18 of 19 subjects reported at least one TEAE, with a total of 99 TEAEs 
reported. No deaths or DLT occurred. The majority (91.9%) of TEAEs were of either mild or moderate 
severity, and 4% were severe (4% of unknown severity). Across all treatment groups, the most 
frequently reported TEAEs (32.32%) involved the SOC of Gastrointestinal Disorders. Five SAEs were 
reported in five subjects. Of the five events, three were severe (breast cancer, abdominal pain, 
organizing pneumonia), and two were of moderate severity (gastric obstruction, hepatic 
encephalopathy). Only one event of gastric outlet obstruction was considered probably related to study 
medication. Although statistical comparisons were not performed, there was no apparent association of 
the number, severity, or relationship of TEAEs with the dose/concentration or number of injections 
administered. Analysis of the response rate of subjects demonstrated that the majority of subjects 
demonstrated stabilization or improvement in calculated volume and/or longest diameter of the cyst. Of 
these subjects, 55.6% showed improvement at Week 12, increasing to 70.6% at Week 24. In addition, 
50% of subjects had a reduction in calculated volume of ≥ 30% at both Week 12 and 24. When 
comparing changes at Week 12 compared to Week 24, 62.5% of subjects showed a further reduction in 
calculated volume compared to Week 12, occurring after single or double injections. Further, of those 
subjects who demonstrated increases in calculated volume at Week 12 compared to baseline, 75.0% 
showed a decrease in calculated volume at Week 24 compared to Week 12, one of which occurred after 
one injection and five after two injections of the 15 mg/mL concentration of NanoPac. 
Ongoing Clinical Studies 
Ongoing clinical trials injecting NanoPac directly into lesions include the following: 
1) Pancreatic tumors via endoscopic ultrasound guided fine needle injection (EUS-FNI) (NANOPAC-
2016-05; NCT03077685).   
 
2.2 
RATIONALE  
This Phase 2 study will include subjects with lung cancer. Only those subjects who are not candidates for 
surgery will be enrolled in the study. The study design allows for a safety evaluation of direct ITU 
injection of NanoPac into lung cancer lesions and associated metastatic lymph nodes.  
Lung cancer cells are particularly sensitive to paclitaxel. Paclitaxel is approved as first-line treatment of 
NSCLC in combination with cisplatin in patients who are not candidates for potentially curative surgery 
and/or radiotherapy.  Similarly, both Taxol and ABRAXANE are FDA-approved first-line treatments of 
locally advanced or metastatic NSCLC, in combination with carboplatin, in patients who are not 
candidates for potentially curative surgery and/or radiotherapy.  
In order to inject lung cancer directly, a minimally invasive procedure known as EBUS-TBNI is proposed 
for this Phase 2 study. The safety and feasibility of this procedure have been demonstrated in numerous 
studies (Lu 2015, Mehta 2015, Mehta 2017). 


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In contrast with IV administration, direct injection of paclitaxel should allow for higher concentrations of 
drug to target local disease with reduced systemic toxicity. ITU NanoPac is expected to be more effective 
than IV paclitaxel, as EBUS-TBNI may bypass the fibrotic stroma that acts as a barrier to IV 
chemotherapy. NanoPac may also allow for prolonged residence and dissolution within the tumor 
tissue, resulting in continuous and greater paclitaxel concentrations in the tumor site.  
Multiple clinical studies have been published demonstrating the use, efficacy, and safety of ITU injection 
of cytotoxic compounds. Cisplatin has demonstrated safety and efficacy when administered repeatedly 
on a weekly basis for 4 weeks at concentrations of 4 mg/mL and up to 40 mL per injection session for 
Malignant Airway Obstruction (MAO) (Ҫelikoğu 2006, Mehta 2015). The same dose regimen of cisplatin 
was used in patients with recurrent lung cancer (≥ 1 site; tumor and/or nodal) in patients who had 
received prior radiotherapy, with good efficacy and safety (Mehta 2017). 
ITU liposomal paclitaxel (1 – 3 mg/mL concentrations) has been administered twice, one week apart, in 
combination with IV carboplatin and gemcitabine to 48 patients with unresectable stage III NSCLC with 
good efficacy and safety outcomes (Lu 2015). 
An ITU cocktail of drugs was administered to 93 patients with non-resectable MAO with primary or 
recurrent malignancy (Ҫelikoğu 1997). The cocktail comprised 5-FU (50 mg/mL), mitomycin (1 mg/mL), 
methotrexate (5 mg/mL), bleomycin (10 mg/mL), and mitoxantrone (2 mg/mL). Volumes of 1 -3 mL were 
injected every 1 -3 days until patency of the airways was restored; the average number of treatment 
sessions was 4 (range 1 – 6) over a 2 week period. In those with recurrent malignancy, ITU injections 
were performed weekly for 6 – 10 weeks, and then every 1 – 3 months if patency was maintained.  
Dosing was stopped if patency not maintained or established after 6 successive ITU injections. Eight of 
93 patients were slightly febrile on day of injection. There were no episodes of pneumonitis, marrow 
suppression, inflammation, nausea, depilation, or clinically important AEs. 
The PK of FDA approved Taxol shows a standard IV dose of paclitaxel of 175mg/m2 BSA administered 
over 3 hours results in a Cmax of 3,650 ng/mL (Paclitaxel Package Insert). In the completed prostate 
cancer study, ITU injection of a mean dose of 53.6 mg NanoPac in a 15 mg/mL concentration resulted in 
Cmax of 19 – 20 ng/mL at the earliest recorded timepoint i.e. 1 hour post-injection. By day 28, levels were 
still measurable at a mean 0.057 ng/mL. (LLOQ = 0.025 ng/ml). Studies in ITU injection of NanoPac in 
pancreatic cancer and intralesional injection in pancreatic cyst are ongoing. However, in the pancreatic 
cyst study, preliminary information shows an average dose of 84.37 mg NanoPac in a 15 mg/mL 
concentration results in a plasma Cmax of 0.24 ng/mL two hours after injection. In the pancreatic cancer 
study preliminary information indicates an average dose of 53.375 mg NanoPac in a 15 mg/mL 
concentration results in a Cmax of 3.19 ng/mL one hour after injection.  
In this study, NanoPac will be administered at a concentration of 15 mg/mL directly into the tumor at a 
volume up to 20% of the total tumor and lymph node volume(s), up to a maximum of 40 mL. Subjects 
will therefore be enrolled with maximum tumor volumes 200 mL i.e. a maximum dose of 600 mg or 10 
mg/kg in a 60 kg subject. Injection volumes up to 20% of tumor volume has been demonstrated to be 
safe in completed and ongoing studies with ITU injections of NanoPac into prostate and pancreatic 


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cancer, as well as pancreatic cyst. The maximum tumor (and node) volume for injection is therefore 200 
ml, which includes the combined volume of up to 2 lung tumor lesions (1 primary and 1 secondary) and 
metastatic lesions to local/regional lymph nodes. 
Since systemic absorption from ITU injections of NanoPac has been confirmed to be significantly low 
compared to IV infusions, a patient in this study administered a maximum single ITU treatment of 600 
mg NanoPac is expected to achieve a Cmax of at least 9 times less paclitaxel than a breast or ovarian 
cancer patient treated with a single IV infusion of 175 mg/m2 Taxol (assuming 100 % bioavailability for 
an ITU dose and linear PK). 
Overall, the ITP injection studies provide the most relevant indirect evidence of expected toxicity when 
injecting NanoPac directly into lung tumors. The observed effects were typically minimal to mild in 
severity, and likely secondary to leakage of paclitaxel. Systemic exposure at the highest dose of 28.8 
mg/kg is orders of magnitude below that achieved after conventional IV doses of paclitaxel. Local 
toxicity and systemic exposure after injection of lung tumors is expected to be similar to ITP injections. 
Given the systemic exposure after ITU injection of prostate and pancreatic cancer, and pancreatic cyst, 
systemic exposure after 40 mL of ITU NanoPac is expected to remain well below levels seen from IV 
chemotherapy. 
2.3 
POTENTIAL RISKS AND BENEFITS  
2.3.1 
KNOWN POTENTIAL RISKS  
There are no known potential systemic risks from the ITU injection of NanoPac into lung tumors. The 
injection procedure itself includes risks related to the sedation and/or anesthesia required for the 
procedure, bronchospasm, hemorrhage from the injection, and possible leakage of NanoPac from the 
injection site into the conducting airways. 
2.3.2 
KNOWN POTENTIAL BENEFITS  
There are no known potential benefits of ITU injection of NanoPac. However, paclitaxel formulated as 
Taxol and Abraxane are both FDA-approved as first-line treatment of locally advanced or metastatic 
NSCLC, in combination with carboplatin, in patients who are not candidates for potentially curative 
surgery and/or radiotherapy.  
3 
OBJECTIVES AND PURPOSE 
The primary objective of this study is to evaluate the safety and tolerability of NanoPac injected into 
lung cancer lesions by EBUS-TBNI on multiple (up to three) occasions, each injection procedure 
administered 4 weeks apart.  Safety and tolerability will be assessed for 24 weeks following first 
NanoPac injection; with additional follow-up at weeks 38 and 52. 


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Secondary objectives are: 
a) To describe the PK of NanoPac when administered into the tumor(s) within the lung;  
b) To evaluate effect on progression free survival (PFS) and overall survival (OS) in this population; and  
c) to assess changes in the treated lesion (and lymph nodes) via CT scan imaging, histology, and 
immunochemistry (IHC). 
4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
In this open-label Phase 2 trial, subjects with lung cancer will be receiving standard of care (SOC) 
treatment, and will be enrolled after confirmation of adequate hematologic function (see Section 5.1).  
Subjects will receive NanoPac via EBUS-TBNI to up to two lung lesions and their associated nodes (at the 
Investigator’s discretion).  
Subjects will be followed for safety during the 24 weeks following first NanoPac injection.   
Subjects will be followed for signs of preliminary efficacy by assessment of tumor response classified 
according to RECIST 1.1 criteria, with tumor size assessed by CT imaging at baseline (Screening), prior to 
each injection, and at Weeks 12, 18, 24, 38, and 52.  Subjects will also be assessed for quality of life 
(QOL) changes using the EQ-5D QOL questionnaire and PFS. 
The lesion(s) to be treated must have been captured via imaging within 4 weeks of study entry.  Follow-
up scans will be performed at Weeks 12, 18, 24, 38, and 52 to provide information on tumor response to 
the injections. The CT scan must provide a demonstrated measurement (3-dimension) for volume 
calculation. The volume calculation will be made using the ellipsoid formula:  V = 1/6 x π x l x w x d. 
The tumor diameter and volume measurement(s) will be determined from this imaging and recorded in 
the source and in the electronic data capture system (EDC).  The CT imaging at Weeks 12, 24, 38, and 52 
will be used for RECIST purposes, for the secondary endpoint assessment of tumor response and PFS. 
Subjects will be enrolled to receive up to three injection procedures with 15 mg/mL NanoPac, each 
injection 4 weeks apart, in up to two parenchymal lung lesions and associated local/regional lymph 
nodes, up to a maximum of 20% of the tumor and lymph node volume, individually and/or in total. A 
maximum of 40 mL of NanoPac will be injected in one procedure. If more than one lesion is present in 
the lung and more than one lesion is planned to be treated, the Investigator will select a primary or 
target lesion. Depending on the amount of NanoPac used for injection of the primary/target lesion, the 
remaining NanoPac may be administered into a second lung tumor lesion and/or metastatic lymph 
nodes up to a maximum volume of 40 mL of NanoPac.  
For example, the sum of the volumes of lesions to be injected at baseline is 200 mL, from which the 
maximum volume allowed to be injected during any single bronchoscopic procedure is 40 mL. In the 


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case of a primary lesion of 6 cm diameter, the volume of the lesion will be 113.1 mL, allowing for an 
injection volume of 22.62 mL of 15 mg/mL NanoPac. This leaves 17.38 mL (40 mL – 22.62 mL) of 
NanoPac available for injection into local/regional lymph nodes (LNs) and/or the second tumor where 
applicable. For a primary lesion with a 3 cm diameter, 2.83 mL of NanoPac may be injected into the 
primary, leaving 37.17 mL of NanoPac available for injection of draining LN’s and/or a second tumor.  
The sequence of injections of tumor lesions will be prioritized according to the general principle of 
treating the primary lesion and associated metastatic node(s) before treatment of a second lesion and 
its associated metastatic node(s).  The sequence of prioritization is therefore the following: 
1) Primary tumor + local LN drainage i.e. N1 nodes first, then N2, then N3 if no contralateral 
nodules (M1a); 
2) Ipsilateral second tumor, where relevant, + local drainage i.e. N1 nodes first, then N2, then N3 if 
no contralateral nodules (M1a); or 
3) Contralateral second tumor (M1a except pleural/pericardial nodules or effusions), where 
applicable, + local drainage i.e. N1 nodes first, then N2. 
The Investigator may use his/her discretion, on a subject-by-subject basis, to inject the entire tumor 
volume available or to use a lesser amount as he/she deems necessary for each individual subject’s 
safety, subject to the above limits.  
Plasma samples will be taken on each day of injection, prior to injection and at 1, 2, and 4 hours after 
the start time of NanoPac injection, as well as at all other study visits up to Week 24 to characterize the 
PK of ITU NanoPac.  
Blood will also be drawn and sent to a central laboratory for flow cytometric (FCM) analysis of immune 
markers prior to each injection (Day 1, Week 4, and Week 8) and at the follow-up visits occurring at 
Week 12, Week 18, and Week 24. 
Lung lesion biopsies for histopathology may be obtained at the time of injection, prior to administration 
of NanoPac. Biopsies must not, however, be obtained from any lesions that are in proximity to cardiac or 
any vital neurovascular structures.  Routine processing for histopathology may be performed at the local 
institution; if only one biopsy is obtained, slides will be provided to the central laboratory for IHC 
staining and reporting, and a portion of the biopsy material will be stored frozen for batch shipping to a 
central laboratory for evaluation of paclitaxel presence.   
4.2 
ENDPOINTS 
4.2.1 
PRIMARY ENDPOINT 
The primary endpoint will be safety and tolerability, as assessed by AEs, changes in vital signs, laboratory 
results, and changes in physical examination following NanoPac injection up to Week 24. 


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4.2.2 
SECONDARY ENDPOINTS 
The secondary endpoints will be: 
• 
Concentration of paclitaxel in the systemic circulation post-injection (as determined by PK analysis); 
o If tissue biopsy samples are obtained prior to any NanoPac injection tissue will also be 
evaluated for the presence of paclitaxel; 
• 
PFS as assessed using (RECIST v1.1; Eisenhauer 2009) and OS to Week 52 with a focus on the week 
24 summaries; 
• 
Assessment of tumor response (dimensions, volume) as determined by CT scan imaging, at Weeks 
12, 24, 38, and 52 compared to baseline;    
o Any changes in characteristics of lesion/nodes as determined via CT scan. 
4.2.3 
EXPLORATORY ENDPOINTS 
• 
Change in Eastern Cooperative Oncology Group (ECOG) Performance Status at Weeks 12 and 24 
compared to baseline; 
• 
Changes in pain (as measured by the visual analog scale [VAS]); 
• 
Changes in QOL as measured by the EQ-5D Quality of Life Scale at baseline and at Weeks 4, 8, 12, 
18, 24, 38, and 52; 
• 
Immune markers will be assessed in the blood via FCM, and in the tissues via IHC.  
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 and able to tolerate the EBUS-TBNI procedure; 
• 
Histologically/cytologically confirmed lung cancer. Eligible subjects may include, for example: 
primary or recurrent non-resectable disease, locally advanced stages II and III with nodal 
disease, stage IV advanced disease 
• 
At least one lesion documented via imaging (within 4 weeks of Screening) which can be accessed 
using EBUS-TBNI; 
• 
Subject is not a candidate for surgery; 
• 
Has received or plans to receive SOC chemotherapy; adequate hematologic recovery must be 
confirmed according to the institution’s SOC;  
• 
Performance Status (ECOG) 0-2 at study entry; 
• 
Life expectancy of at least 6 months; 
• 
Adequate marrow, liver, and renal function at study entry; 
o ANC ≥ 1.5 x 109/L; 
o Hemoglobin ≥ 9.0 grams/dL; 


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o Platelets ≥ 75 x 109/L; 
o Total bilirubin ≤ 1.5x institutional ULN; 
o AST/ ALT ≤ 2.5x institutional ULN; 
o Creatinine ≤ 1.5x institutional ULN; 
• 
Appropriate steps taken to minimize or avoid the potential for pregnancy for subjects of child-
bearing potential.* 
* Note: A female patient is considered to be of childbearing potential unless she has had a 
hysterectomy, is at least one year postmenopausal or has undergone tubal ligation. For the purposes of 
this study, adequate birth control includes at least one medically approved and highly effective method 
of birth control, defined as those which result in a low failure rate (i.e., < 1% per year) when used 
consistently and correctly, such as implants, injectables and oral contraceptives combined with the use 
of double condoms. Only male patients whose vasectomy has been confirmed by semen analysis at least 
3 months after the vasectomy are allowed not to use acceptable contraceptive methods. 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
If a subject meets any of the following criteria, he or she must be excluded from the study: 
• 
Significant cardiac disease (Class III or IV per New York Heart Association guidelines); 
• 
Active bacterial, viral, or fungal infections (including active AIDS, hepatitis B or hepatitis C); 
• 
Symptomatic central nervous system (CNS) metastasis which are neurologically unstable, or CNS 
disease requiring increase in steroid dose (treated metastatic disease and stable steroid use are 
not excluded); 
• 
Known hypersensitivity to study agent; 
• 
Pregnant or breastfeeding women. 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Sufficient subjects will be screened to allow up to 18 subjects to be enrolled in the trial. Subjects will be 
recruited at up to five study sites. It is not anticipated that any advertising will be required for recruiting 
to the study.  
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION 
Subjects are free to withdraw from participation in the study at any time upon request. The reason for 
wanting to withdraw will be documented in the source notes and in the EDC. The final study visit is 
planned for six months after NanoPac injection. For subjects wishing to pursue other treatment options 
(such as other clinical trials) sooner than 12 months after NanoPac injection, the final study visit may be 
conducted sooner.  


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• 
The Investigator, at their discretion, may elect not to administer the second or third injection or 
reduce the volume of the injection.  All subjects will be followed for safety for the duration of 
the trial unless informed consent is withdrawn.  It is very important that any events occurring be 
captured and followed for the safety of the subject.  
• 
Subjects may be non-compliant with the study protocol in a way that much of the data is not 
captured which would usually require withdrawal for non-compliance; however, any data points 
missed would be considered “missing data.” A subject would not be withdrawn in this situation. 
 
• 
Clinical AE, laboratory abnormalities, or other medical conditions/situations may occur which 
would usually require withdrawal from a study. In this instance it is very important that all of 
these events be captured, followed, and documented, and therefore a subject would not be 
withdrawn but would continue to completion. 
Should the Investigator feel it to be in the best interest of the subject for them to be withdrawn from 
the study, or if another clinical trial is being considered for the subject, 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 before Week 24 they would complete all assessments for Week 24; if 
they withdraw after Week 24, they would complete the assessments which would be performed at 
either the Week 38 or Week 52 visit.  
 
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 terminate if there is sufficient reasonable 
cause. Written notification, documenting the reason for the study suspension or termination, will be 
provided by the suspending or terminating party to Sponsor. If the study is prematurely terminated or 


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suspended, the PI will promptly inform the IRB and will provide the reasons for the termination or 
suspension. 
Circumstances that may warrant termination include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants; 
o Routine Medical Monitoring determining a requirement for an ad hoc meeting of the 
Safety Review Committee (SRC), and/or routine SRC reviews, will allow for termination 
of study based on unacceptable risk, which will consider all safety evaluations and DLTs.   
• 
Insufficient compliance with protocol requirements; 
• 
Data that are not sufficiently complete and/or evaluable; 
• 
Determination of futility. 
The study may resume once concerns about safety, protocol compliance, and data quality are addressed 
and satisfy the Sponsor, IRB, and/or FDA. 
6 
STUDY AGENT 
 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
6.1.1 
ACQUISITION 
NanoPac will be manufactured by CritiTech, Inc. (Lawrence, KS) and provided for use in this study. Study 
agent will not be shipped to the study site until all regulatory documentation has been provided by the 
site and the site is ready for study initiation, at which time the study agent will be released for shipment. 
Shipment will be via courier, temperature controlled at 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 (Section 6.1.3). 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
NanoPac is presented as a white powder, provided in a sealed vial within a study kit. 
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 


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on the reconstitution of the drug, the storage of the drug once reconstituted, the dose withdrawal 
procedure, and the timeline permitted between reconstitution and use. 
The vial will be labelled to include details as follows:  
“NanoPac (sterile nanoparticulate paclitaxel) Powder for Suspension. 306mg per vial. Lot no.: 
XXXXXXXXXXX Caution: New Drug – Limited by federal law to investigational use. For single use only. 
Manufactured by: CritiTech Inc., 1849 East 1450 Road, Lawrence, KS, 66044.” 
The carton will be labeled with information indicating the contents as follows: 
“Each kit contains: 1 vial of NanoPac (sterile nanoparticulate paclitaxel) Powder for Suspension, 306 mg 
per vial; 1 vial Sterile Reconstitution Solution for NanoPac Powder for Suspension, 7 ml per vial; 1 
instruction sheet for the reconstitution of the NanoPac dosing suspension and the dose withdrawal 
procedure.” 
6.1.3 
PRODUCT STORAGE AND STABILITY 
Prior to administration at the hospital/clinic, the dry, sterilized NanoPac vials will be stored at the clinical 
site’s pharmacy, temperature controlled at 59˚ to 86˚F (15˚ to 30˚C). 
Once the NanoPac has been reconstituted, it will be delivered to the clinic for use. Reconstitution will 
occur in the pharmacy at the clinical site, and if the reconstituted agent is not being delivered 
immediately the syringe may be stored according to the IFU until delivery. Each vial used and each 
syringe must be labelled with the subject’s ID and visit information for accountability purposes. 
6.1.4 
PREPARATION 
A prescription will be provided for each subject detailing the subject ID and the date and time required 
for administration. This will be provided to the Pharmacy at least 24 hours prior to administration time. 
Once the drug has been reconstituted to the required volume at 15mg/mL the injection volume will be 
withdrawn, as described in the IFU, from the vial(s) into one or more syringes up to a maximum volume 
of 40 mL.  
The maximum volume for the first injection will be calculated from the baseline CT measurements prior 
to first injection. Actual amounts injected to the various lesions will be detailed in the source and in the 
EDC.  
The syringe(s) for administration will be labeled with the subject ID and the date and time of 
preparation.  
6.1.5 
DOSING AND ADMINISTRATION 
Subjects will receive NanoPac on three occasions: on the Day 1, Week 4, and Week 8 visits. 


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On the day of NanoPac administration, the subject will receive parenteral antibiotic prophylaxis at the 
discretion of the Investigator. The subject will be sedated by standard institutional anesthetic procedure 
for the bronchoscopic procedure and injection of NanoPac. At each injection visit tumor size(s) will also 
be measured using EBUS-TBNI, and the tumor(s) and node/nodal sizes recorded.  
EBUS-TBNI of the tumor(s) and node(s) within the lung will be used to inject 15 mg/mL NanoPac at a 
volume up to 20% of tumor and node volume for each individual lesion or metastatic node (as 
calculated in Section 4.1), up to a maximum volume of 40 mL during each injection procedure.  
For the first injection procedure, the tumor volume (lung and nodal lesions) will be calculated from the 
baseline CT information. The injection volume for the second and third injection procedures should be 
identical to the first injection procedure, but may be reduced per Investigator discretion. The volume of 
NanoPac injected, total and/or lesional, will at no time be increased beyond the maximum as calculated 
by the baseline CT measurement(s) and may be reduced at discretion of Investigator.   
The stylet will be removed from a 22-gauge fine needle aspiration (FNA) needle and the needle filled 
with the study treatment, NanoPac, from the syringe provided. The needle will be luer locked into the 
accessory channel of the echoendoscope. Doppler ultrasound imaging will be used to verify lack of 
intervening vascular structures in path to tumor. NanoPac will be injected ensuring that NanoPac is 
dispersed evenly throughout the entirety of the tumor.  
6.1.6 
ROUTE OF ADMINISTRATION 
NanoPac will be administered directly into the tumor(s) and node(s) within the lung via EBUS-TBNI.  
6.1.7 
DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
Enrollment of the first three subjects will be sequential. After the first subject has completed the 2-week 
follow-up visit after their first injection procedure, the SRC will convene a teleconference with the 
Principal Investigator to review the safety of NanoPac and approve dosing of the second subject 
provided there are no safety issues of note. The second subject may be consented and undergo 
Screening activities prior to SRC approval but may not be treated with NanoPac until the SRC has given 
approval. The SRC may also determine at their discretion, upon review of routine data, that 
dose/volume reduction is required for the remaining subjects in this study. This sequence of safety 
review will be repeated for the second and third subjects, after which enrollment will be open for all 
remaining subjects. 
It is possible that the full 20% tumor (or lymph node) volume for a particular subject will not be able to 
be administered; the Investigator will determine this at the time of injection. In the event that not all of 
the calculated volume of NanoPac can be administered, particularly with respect to the primary target 
lesion, the amount not injected will be available for use in other lesions or nodes identified on the 
baseline CT, provided that the maximum volume injected into any lesion or node is not more than 20% 
of the volume of the lesion or node, up to a maximum of 40 mL in total per bronchoscopic procedure.  


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All lesions to which NanoPac is delivered will be documented in the source and in the EDC, and only the 
lesions injected at the first procedure may be injected at the second and third procedure, however the 
amount delivered may differ but must not exceed 20% of lesion volume as calculated from the baseline 
CT scan. 
6.1.8 
DURATION OF THERAPY 
NanoPac will be administered on up to three occasions 4 weeks apart.  
6.1.9 
TRACKING OF DOSE 
Volume of NanoPac injected to any lesion or node will be documented within the source and the EDC. 
6.1.10 DEVICE SPECIFIC CONSIDERATIONS 
Not applicable. 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
The Investigator will maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the study agent, including the date, quantity, batch or code number, and identification of 
subjects (number, initials) who received study 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.  
The Investigator will document the amount of NanoPac injected into each lesion and node, and any 
volume of NanoPac remaining unused, in the source document and in the EDC. 
Under no circumstances will the Investigator supply clinical material to other Investigators or clinicians 
or allow the supplies to be used other than as directed by this protocol without the consent of the 
Sponsor.  
7 
STUDY PROCEDURES AND SCHEDULE 
 
7.1 
STUDY PROCEDURES/EVALUATIONS 
 
7.1.1 
STUDY SPECIFIC PROCEDURES  
The following procedures and evaluations will be done as part of this study. 
• 
Screening procedures/evaluations as described in Section 7.3.1.  


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• 
Confirmation of adequate hematologic recovery (see Section 5.1 Participant Inclusion Criteria) 
must be obtained prior to NanoPac administration and 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); 
• 
A CT scan will be conducted during the screening period prior to first injection, in order to 
calculate tumor and node volume(s). CT scans will also be conducted prior to the second and 
third injections (Weeks 4 and 8) and at follow-up visits at Weeks 12, 18, 24, 38, and 52. Should 
the subject withdraw from the study at any time, a scan will be conducted as part of the End of 
Study procedures if possible. 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. The baseline CT scan will be provided to the Medical Monitor for review/approval with 
the completed pre-injection form prior to first injection for all subjects.  All imaging will be filed 
in the subject record and identifiers removed before images are shared with the Sponsor. 
• 
Samples will be collected and processed for PK evaluation (Section 7.2.2); 
• 
Samples will be collected and processed for routine clinical laboratory assessment (Section 
7.2.1). 
• 
Samples will be obtained and sent to a central laboratory for FCM evaluation of immune 
markers (Section 7.2.2). 
• 
A biopsy specimen from the primary target lesion may be obtained at each injection visit; 
biopsies must not, however, be obtained from any lesions that are in proximity to cardiac or any 
vital neurovascular structures.  If available, a portion will be prepared on slides to be sent to a 
central laboratory for IHC assessments and a portion will be stored frozen prior to bulk shipment 
to a central laboratory for evaluation of paclitaxel levels. 
• 
QOL will be assessed using the EQ-5D QOL questionnaire (Section 7.2.2). 
• 
Pain will be assessed with the VAS at screening, on the days of NanoPac administration (pre- and 
post-injection), and at all other study visits up to Week 24. 
• 
NanoPac administered via EBUS-TBNI-guided fine needle injection (Section 6.1.5). 
7.1.2 
STANDARD OF CARE STUDY PROCEDURES  
The subjects being enrolled to this study will have received or will be receiving concomitant SOC as 
required for their care; platelet and neutrophil recovery is required to meet inclusion criteria for 
participation.  
Following administration of NanoPac, the care of the subject will be as dictated by the protocol but will 
allow for any other standard care the Investigators would routinely provide (such as pain relief, 
additional clinic visits, etc.).  
Information on SOC and treatment post-injection(s), until the End of Study visit, will be captured as 
appropriate. 


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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 days of NanoPac injection, 
2 weeks after each injection, and at the Weeks 12, 18 and 24 visits.  The samples to be collected 
are: sodium, potassium, chloride, carbon dioxide (CO2), calcium, phosphorus, glucose, blood 
urea nitrogen (BUN), creatinine, alkaline phosphatase, total bilirubin, direct bilirubin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), 
lactate dehydrogenase (LDH), total protein, albumin, and calculated creatinine clearance; 
• 
Red blood cell count (RBC), hemoglobin (Hgb), hematocrit (Hct), 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; and urine pregnancy test (if applicable at Screening, Week 12 and Week 24); 
• 
Prothrombin time (PT), activated partial thromboplastin time (PTT), and international 
normalized ratio (INR). 
• 
Serology testing will be performed for HIV, Hepatitis B and Hepatitis C prior to first injection 
7.2.2 
OTHER ASSAYS OR PROCEDURES 
PK samples will be taken at scheduled injection  visits (Day 1, Week 4, and Week 8), prior to NanoPac 
injection, and at 1, 2, and 4 hours +/- 10 minutes post injection start time.. A single sample will be 
obtained during all other study visits, up to and including Week 24.  
Imaging with CT scan will occur prior to each injection of NanoPac, and at Weeks 12, 18, 24, 38, and 52. 
Should the subject withdraw from the study at any time, a scan will be conducted as part of the End of 
Study procedures if possible. Additional imaging may be performed at the Investigator’s discretion and 
all resulting images will be collected for the subject’s record.  The baseline CT scan will be forwarded to 
the Medical Monitor for review/approval with the completed pre-injection form prior to first injection 
for all subjects.  All imaging will be collected for the subject’s record and identifiers removed before 
sharing copies with the Sponsor. 
Pain assessment will be conducted with the VAS at all study visits to Week 24. On the day(s) of NanoPac 
administration the pain assessment will be conducted prior to NanoPac injection, and at 4 hours post-
injection or just prior to discharge following the procedure to allow for residual anesthetic effects to 
wear off. 
QOL assessment will be conducted using EQ-5D QOL instrument at baseline, at each injection visit prior 
to the procedure, and again at Weeks 12, 18, 24, 38, and 52. 


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Blood samples will be collected for flow cytometric evaluation of immune markers at each injection visit 
and again at Weeks 12, 18, and 24. 
Biopsy specimens may be collected at each or any injection visit and a portion will be prepared on slides 
for IHC assessment and a portion will be stored frozen for paclitaxel assessment. 
7.2.3 
SPECIMEN PREPARATION, HANDLING, AND STORAGE 
PK samples will be drawn at the specified time/visit, prepared and stored frozen on-site until batch-
shipped to Covance Laboratories (Madison, WI) for analysis. Procedures for processing for storage will 
be provided prior to study initiation. 
Biopsy specimens for paclitaxel assessment, when available, will be stored frozen on-site until batch-
shipped to Covance Laboratories (Madison, WI) 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 entry to the EDC. 
Blood samples for FCM will be drawn into tubes provided for this purpose, and shipped to NeoGenomics 
on the day the sample is obtained; samples may remain at ambient temperature until shipped. 
Biopsy specimens for IHC evaluation, when available, will be sent to the site’s pathology laboratory for 
preparation of tissue block/slides to be shipped to NeoGenomics. A manual will be provided by 
NeoGenomics detailing the instructions for both slide preparation and for FCM sample preparation.  
7.2.4 
SPECIMEN SHIPMENT 
Routine laboratory samples will be sent to the local laboratory upon collection.  
Shipment process for the PK samples, for the FCM samples, and for the slides for IHC evaluation, will be 
provided once established with the laboratories, prior to study initiation, and details will be provided to 
the site in their Regulatory Binder. 
7.3 
STUDY SCHEDULE 
7.3.1 
SCREENING 
The following procedures and assessments must be completed, documented and reviewed by the 
Investigator during the screening period, within 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, and demographics; 


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• 
Review and documentation of lung cancer, including documentation of lesion size(s) as 
determined by imaging; diagnosis and previous treatments including surgical and 
chemotherapeutic records. A copy of the pathology report confirming the diagnosis must be 
filed in the subject’s study record;  
• 
Review and documentation of all concomitant prescription and non-prescription medications; 
• 
Comprehensive physical examination, including ECOG Performance Status assessment 
(Appendix A), and vital signs (blood pressure, heart rate, temperature, body weight and height); 
• 
Visual analog scale for pain assessment; 
• 
Sample collection and processing for clinical laboratory assessments (Section 7.2.1);  
• 
Urine pregnancy test for women of child-bearing potential; 
• 
Imaging with CT scan will be performed prior to the next study visit; the scan may be performed 
any time within 28 days of the injection visit, allowing for sufficient time to obtain the 
dimensions for all lesions and nodes planned to be injected.  This information is required for the 
NanoPac requisition to Pharmacy indicating the volume required for Day 1 procedures.  The 
baseline redacted CT scan will be forwarded to the Medical Monitor for review/approval with 
the completed pre-injection form prior to first injection for all subjects.   
Visit dates will be scheduled/projected forward from the first injection visit at Day 1. 
Visits from Week 1 to Week 10 will have a +/- one day window; Weeks 12, 18 and 24 will allow for a +/- 
1-week window; Weeks 38 and 52 will allow for a +/- 2-week window 
7.3.2 
DAYS OF NANOPAC INJECTION – DAY 1, WEEK 4, WEEK 8 
Day 1: All Screening assessments must have completed prior to this visit, and all results and 
inclusion/exclusion criteria must have been confirmed.  
All injection visits – Day 1, Week 4, Week 8, prior to the bronchoscopic procedure: 
• 
Subjects will complete an EQ-5D QOL questionnaire 
• 
Comprehensive physical examination, including vitals and ECOG Performance Status assessment 
(Appendix A);  
• 
VAS for pain assessment will be completed pre- and post-injection.  Post-injection scale will be 
completed at the 4-hour PK sample timepoint. 
• 
AEs occurring in the period between Screening and this visit must be confirmed as either 
ongoing or completed. AEs occurring prior to the procedure will be considered history, and 
those occurring after NanoPac administration will be documented separately as TEAE, with a 
start date on or after administration. 
• 
Concomitant medication will be reviewed and updated as necessary; 
• 
Laboratory sample collection prior to injection, and processing for clinical laboratory 
assessments (Section 7.2.1):  
o Routine safety laboratory work and blood sample for FCM 


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 
Coagulation laboratory assessment results must be confirmed to be within 
normal limits prior to injection if a biopsy is planned 
o PK samples pre-injection and 1, 2, and 4 hours post-i injection 
• 
Imaging with CT scan will be performed prior to injections at Week 4 and Week 8 and may be 
obtained up to 3 days prior to the scheduled injection visit.  
Subjects will receive NanoPac as described in Section 6.1.5. Immediately prior to NanoPac injection, 
tissue biopsies will be obtained for routine histopathology at the site (if standard procedure) and for 
paclitaxel assessment and tissue block/slide preparation for IHC assessment.  
7.3.3 
FOLLOW-UP VISITS 
Follow up visits occur one and two weeks after each injection (Weeks 1, 2, 5, 6, 9, and 10) and then at 
Week 12 and at Week 18. 
At all follow-up visits the following are performed: 
• 
VAS for pain assessment will be completed; 
• 
Vital signs will be assessed; 
• 
A single PK sample will be collected; 
• 
Concomitant medications will be updated; 
• 
AEs will be updated. 
At Weeks 2, 6, 10, 12, and 18 routine safety blood samples will be obtained and sent to the local 
laboratory for assessment (Section 7.2.1).  A urine pregnancy test will be performed at Week 12 for 
women of child-bearing potential. 
At Weeks 12 and 18 the following additional assessments will be performed: 
• 
QOL questionnaire will be completed; 
• 
An ECOG score will be obtained; 
• 
A blood sample for FCM analysis of immune markers will be obtained; 
• 
A CT scan will be performed within the visit window.  
 
In the event that an Investigator or subject elects not to receive all three scheduled injections, not all 
study visits listed in the schedule of events are required. The list below clarifies what visits are to be 
conducted when injections are missed. 
− 
Week 4 Scheduled Injection Missed: Week 5 visit is not required; Week 6 is still required. The 
subject will then return at Week 8 for their next injection if all criteria for receiving the injection 
are met. 
− 
Week 8 Scheduled Injection Missed: If Week 8 injection procedure is missed, the one-week 
follow-up (Week 9) is not required but the two-week follow-up (Week 10) is still required. 
− 
Week 4 and Week 8 Scheduled Injections Missed: If a subject misses the Week 4 
administration, they will follow the visit schedule as outlined above in anticipation that the 


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scheduled Week 8 injection may still occur. In the event that the Week 8 injection is also missed, 
the Week 9 and Week 10 visits are no longer required for safety as 2 months have passed since 
investigational drug administration. In this situation, Weeks 5, 9, and 10 are not required. 
7.3.4 
PRIMARY ENDPOINT STUDY VISIT (WEEK 24, APPROXIMATELY 6 MONTHS) 
This primary endpoint visit will be conducted at Week 24 ± 1 week.  For any subject withdrawing prior to 
Week 24 all assessments as described for this visit would be conducted. 
Subjects may decide to withdraw participation prior to this point and at that time this visit should be 
conducted if possible. For some subjects the Week 12 (3-month) or Week 18 study visit may serve as the 
final study visit, as this 6-month visit will only be conducted for subjects still willing and able to undergo 
the assessments. 
At this primary endpoint study visit the following procedures will be performed: 
• 
Comprehensive physical examination, including vitals and ECOG Performance Status 
assessment;  
• 
VAS for pain assessment will be completed;  
• 
QOL questionnaire will be completed; 
• 
Concomitant medications will be updated; 
• 
AE collection up to the Week 24 visit (noted to be resolved or ongoing at this visit); 
• 
Sample collection and processing for clinical laboratory assessments (Section 7.2.1);  
o Routine safety laboratory work and blood sample for FCM; 
o PK sample obtained; 
o Urine pregnancy test for women of child-bearing potential; 
• 
Imaging with CT scan within the visit window. 
7.3.5 
FOLLOW UP VISIT WEEK 38 AND END OF STUDY WEEK 52 
 
These visits are being conducted in subjects still willing and able to undergo assessments for the 
purposes of determining QOL, PFS, and OS. 
 
The following procedures will be performed: 
• 
Vital signs will be performed; 
• 
ECOG will be assessed; 
• 
QOL questionnaire will be completed; 
• 
Imaging with CT scan within the visit window; 
• 
Concomitant medications – only those used as SOC lung cancer therapies will be captured. 
 
For any subjects withdrawing after the Week 24 visit, their withdrawal visit would include all 
assessments noted for these visits. 


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Week 38 and Week 52 visits will be performed with a visit window of +/- 2 weeks. 
 
No further follow-up will be required or requested of subjects after this visit. 
7.3.6 
EARLY TERMINATION VISIT 
In the event a subject is withdrawn prior to Week 24 they would, at minimum, undergo Week 24 
evaluations, which include the procedures described in Section 7.3.4. 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.  If a subject is withdrawn from the study between Week 24 and Week 52, the 
assessments for Week 52 will be conducted. 
7.3.6 
UNSCHEDULED VISITS 
Any unscheduled visits will be documented in the source documents, and any assessments and/or 
evaluations performed will be noted and reviewed. The subject will undergo any other evaluations 
determined necessary by the Investigator to ensure the subject’s well-being. If the Investigator deems it 
necessary for blood work to be done, this information will be transcribed into the EDC, and any imaging 
assessments which may be performed will also be noted in the EDC.  
 


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7.3.7 
SCHEDULE OF EVENTS TABLE  
 
  
Screening6 
Day 1 
Week 1 
  
Week 4 
  
  
Week 8 
  
  
  
  
Week 24 
Week 38 
Week 52 
NanoPac 
Week 2 
NanoPac 
Week 5 
Week 6 
NanoPac 
Week 9 
Week 10 
Week 12 
Week 18 
(6 
months) 
(9 
months) 
(12 
months) 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History1 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Exam 
X 
X 
  
  
X 
  
  
X 
  
  
  
  
X 
  
  
Pain Assessment4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
QOL 
Questionnaire 
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
X 
X 
Vital Signs 
X  
X  
X 
X 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
ECOG2 
X 
X  
  
  
X  
  
  
 X 
  
  
X 
X 
X 
X 
X 
Clinical 
Laboratory 
Tests8,9 
X 
X 
  
X 
X 
  
X 
X 
  
X 
X 
X 
X 
  
  
PK Samples 
(blood)3 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Blood FCM 
analysis 
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X  
  
  
Tissue (biopsy) 
for IHC and 
paclitaxel 
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
Imaging (CT 
Scans)5 
X 
  
  
  
X 
  
  
X 
  
  
X 
X 
X 
X 
X 
NanoPac 
Procedure 
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
Pharmacy  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
Concomitant 
Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7 
X7 
Adverse Events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
 
1 
History includes all events before initiation of NanoPac treatment. 
2 
ECOG Performance Status Scale attached as Appendix A. 
3 
PK Samples on Day 1, Week 4, and Week 8 will be drawn prior to injection and at 1, 2, and 4 hours post-dose. PK samples will also be obtained at each study visit thereafter. 
PK samples within the first 4 hours on Day 1 will allow for a 10-minute window around the samples.  
4 
Pain will be assessed with the visual analog scale. 


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5 
Imaging with CT scan will occur during the screening period, prior to each NanoPac administration, and at Weeks 12, 18, 24, 38, and 52. Should the subject withdraw from the 
study at any time, a CT 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.  
6 
Screening will occur up to four weeks prior to injection. 
7       All concomitant medications will be captured to Week 24. Only SOC lung cancer therapy will be captured at visit Weeks 38 and 52. 
8        Urine pregnancy test for women of child-bearing potential at Screening, Week 12 and Week 24. 
9       Clinical laboratory tests include hematology, chemistry, urinalysis and at screening includes serology (Hepatitis A, Hepatitis B and HIV). 


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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Sponsor acknowledges that EBUS-TBNI of NanoPac into the tumor(s) and node(s) within the lung, 
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 
electronic Case Report Forms (eCRFs). For this protocol, a prescription medication is defined as a 
medication that can be prescribed only by a properly authorized/licensed clinician. Medications to be 
reported in the eCRF are concomitant prescription medications, over-the-counter medications, and non-
prescription medications. 
Although no interaction studies have been conducted using NanoPac, paclitaxel is metabolized by 
cytochrome P450 isozymes CYP2C8 and CYP3A4 (Taxol Package Insert). Thus, there is a potential for 
drug interactions with concomitantly administered substrates (e.g., repaglinide and rosiglitazone), 
inhibitors (e.g., gemfibrozil), and inducers (e.g., rifampin) of CYP2C8. There is also the potential for 
paclitaxel to interact pharmacokinetically with CYP3A4 substrates (e.g., midazolam, buspirone, 
felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, 
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and 
telithromycin), and inducers (e.g., rifampin and carbamazepine). 
7.6 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES  
No precautionary medications, treatments, or procedures are included in this protocol; they may, 
however, be administered at the discretion of the Investigator, anesthesiologist, or the subject’s primary 
care provider or oncologist. All medications will be recorded. 
7.7 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
If chemotherapy or radiation therapy is to be initiated during the conduct of the study, particularly 
during the 4 weeks following the first NanoPac injection, the PI must contact the study Medical Monitor 
to discuss the assessments made in determining the need to initiate therapy, and document date to 
start and medications prescribed. This will all be entered to the EDC at the next study visit, but the 
Medical Monitor must be made aware of this as soon as possible.  
7.8 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
Prophylactic antibiotics will be administered on the day of NanoPac injection and any other prophylactic 
medications will be administered according to the institution’s standard of care. 


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7.9 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
Rescue medications, treatments, and procedures will be performed according to the institution’s 
standard of care, and will be documented in the source documents and in the study data as needed. 
7.10 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Not applicable. 
8 
ASSESSMENT OF SAFETY 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
Safety assessments to be conducted in this study include: 
• 
AEs, collected at all study visits from the time of dosing to Week 24; 
• 
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, SRC review will be conducted as 
follows: 
• 
As described in Section 6.1.7, for only the first three subjects enrolled to the study, the SRC will 
conduct a review after each of the first three subjects completes the 2-week follow-up visit after 
their first injection of NanoPac. Additionally, the SRC will conduct a review after each of the first 
three subjects completes the 2-week follow-up visit after their second injection of NanoPac. 
• 
The baseline redacted CT scan will be forwarded to the Medical Monitor for review/approval 
with the completed pre-injection form prior to first injection for all subjects.   
• 
Thereafter, safety reviews will take place on a monthly basis during the conduct of the study. 
The Medical Monitor will review the data for each subject entered to the database on a monthly 
basis and communicate the summary findings to the SRC at each review.   
• 
The SRC may also convene at any other time if deemed necessary or requested by any member 
of the SRC. 
Included in the SRC’s review of the AEs and general study data pertaining to safety (such as laboratory 
results and questionnaire responses) consideration will be given to any adverse event that is considered 
related or possibly related to NanoPac and therefore is potentially a DLT. The definition of a DLT will be 


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made by consensus by the SRC and Principal Investigator for AEs. DLTs will, in addition, include the 
following: 
• 
≥ Grade 3 febrile neutropenia; 
• 
≥ Grade 3 non-hematological toxicity, unless clearly not attributable to the study agent; 
• 
Grade 3 diarrhea and vomiting lasting more than 72 hours, or Grade 4 diarrhea and vomiting; 
• 
Grade 4 neutropenia lasting 5 days; 
• 
Grade 4 thrombocytopenia; 
• 
Grade 4 biliary toxicity; 
• 
Concomitant elevation of AST/ALT 3x ULN and bilirubin 2x ULN (Hy’s Law) 
• 
Any life-threatening event (unless there is a clear alternative explanation that the event is not 
related with the procedure or the study agent itself); and 
• 
Any clinically important event as defined by the SRC. 
DLTs may result in removal of the subject from study treatment, however they will not be discontinued 
from the study follow-up procedures unless deemed to be in their best interest. 
 
Events of special interest (Section 8.4.4) will be specifically reviewed by the Medical Monitor, and the 
SRC review will provide and document oversight as detailed in the Safety Plan. 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended change in structure, function, signs, 
or symptoms temporally associated with the use of a medicinal product, whether or not related to the 
product. Undesirable changes in laboratory values should not be considered AEs unless they are 
considered symptomatic of a clinical condition or diagnosis, are evaluated as clinically significant, or 
require therapy. Worsening of a pre-existing condition is also considered an AE, as is the discovery of an 
abnormal finding during physical exam that was not included in the medical history. Clinical conditions 
attributable to disease progression will be considered AEs and reported on the eCRF. 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
A Serious Adverse Event (SAE) is any adverse event that meets at least one of following criteria: 
1) 
Is fatal; 
2) 
Is life-threatening, meaning the subject was, in the view of the Investigator, at immediate 
risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it 
occurred in a more serious form or progressed, might have caused death; 
3) 
Is a persistent or significant disability or incapacity; 


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4) 
Requires or prolongs inpatient hospitalization. Inpatient hospitalization will be considered a 
hospitalization that is longer than 24 hours, or a hospitalization that requires an intervention 
to treat emergent symptomatology (non-diagnostic); 
5) 
Is a congenital anomaly or birth defect; 
6) 
Other important medical events may be considered a serious adverse experience when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes as listed in #1-5 in 
this definition. 
8.1.3 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
As this is a Phase 2 study, all unanticipated problems will be captured as either AEs or SAEs and will be 
defined and reported accordingly. 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 
SEVERITY OF EVENT 
Signs and symptoms will be graded by the Investigator according to the NCI CTCAE v 5 grades; Grades 1 
through 5 have unique clinical descriptions of severity for each AE based on the general guideline as 
follows: 
• 
Grade 1 - Mild:  Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 - Moderate:  Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
• 
Grade 3 - Severe:  Or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living 
• 
Grade 4 - Life-Threatening:  Urgent intervention indicated 
• 
Grade 5 - Fatal:  Death related to the adverse event.  
8.2.2 
RELATIONSHIP TO STUDY AGENT 
The following five-point scale will be used by the Investigator to rate the relationship of the AE to the 
study agent: 
• 
Definitely related: A clinical event (including laboratory test abnormality) occurring in a plausible 
time relationship to drug administration, and which cannot be explained by concurrent disease or 
other drugs or chemicals. The response to withdrawal of the drug (de-challenge) should be 
clinically plausible. The event must be definitively associated pharmacologically, using a 
satisfactory re-challenge procedure, if necessary;  
 


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• 
Probably related: A clinical event (including laboratory test abnormality) with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and which follows a clinically reasonable response on withdrawal (de-
challenge). Re-challenge information is not required to fulfill this definition; 
 
• 
Possibly related: A clinical event (including laboratory test abnormality) with a reasonable time 
sequence to administration of the drug, but which could also be explained by concurrent disease 
or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear; 
 
• 
Unlikely to be related: A clinical event (including laboratory test abnormality) whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event did 
not occur within a reasonable time after administration of the trial medication) and in which other 
drugs or chemicals or underlying disease provides plausible explanations (e.g., the subject’s 
clinical condition, other concomitant treatments); 
 
• 
Not related: An event for which sufficient information exists to conclude that the etiology of the 
event is unrelated to the study agent. An alternative definitive etiology should be documented by 
the Investigator. 
8.2.3 
EXPECTEDNESS  
The definition of expectedness is related to the study agent specifically. An event may be unexpected 
in the subject but that in itself does not qualify as unexpected; review against information available and 
provided for the study agent is what will determine expectedness. 
Sponsor will be responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study agent, in the protocol and within the Investigator’s 
Brochure. 
 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
AEs will be recorded throughout the study to Week 24, and at early termination if it occurs sooner. AEs 
ongoing at the Week 24 study visit must be followed until resolution or until the Investigator determines 
them to be stable and/or adequately managed.  
Subjects will be required to spontaneously report any AEs. Study personnel will ask open-ended 
questions to obtain information about AEs at every visit. Date and time of onset and resolution (if 
applicable) of the AE will be documented. 
All SAEs must be followed until the event resolves or, in the opinion of the Investigator, becomes stable. 
  


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8.4 
REPORTING PROCEDURES 
8.4.1 
ADVERSE EVENT REPORTING  
All AEs (whether or not attributable to the study agent) occurring during the 24 weeks following first 
NanoPac injection observed by the Investigator or reported by the subject will be recorded on the eCRF. 
The following information will be recorded for all AEs: 
• 
Name of condition/diagnosis/description; 
• 
Onset and resolution dates; 
• 
Severity; 
• 
Relationship to study agent; 
• 
Action taken; 
• 
Seriousness.  
8.4.2 
SERIOUS ADVERSE EVENT REPORTING  
All SAEs, including death, due to any cause which occurs during the 24 weeks following first NanoPac 
injection, whether or not expected and regardless of relationship to study agent, must be reported to 
the Medical Monitor immediately upon discovery of the event, using the SAE reporting form, by email or 
fax and, if necessary, by phone to: 
Dr. Antony Verco 
Medical Monitor 
Email: tony.verco@usbiotest.com 
Phone: 805-235-9193 
24-hour Emergency Contacts: 
Gere diZerega, MD 
or 
Antony Verco, MD 
 
 
 
 
Medical Director 
 
Medical Monitor 
 
 
 
 
805-630-2800   
 
805-235-9193 
The Study Manager should be copied on all correspondence. 
The Sponsor will advise the Investigator regarding the nature of any further information or 
documentation that is required. The Investigator should provide the following documentation at the 
time of notification if available: 
• 
SAE Report Form; 
• 
Concomitant and support medication pages; 
• 
Relevant diagnostic reports; 
• 
Relevant laboratory reports; 
• 
Admission Notes; 
• 
Hospital discharge summary (when available). 


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8.4.3 
UNANTICIPATED PROBLEM REPORTING  
Unanticipated incidents or events that occur during the first 24 weeks of the study and meet the criteria 
for an AE or SAE will be captured in the source documents and in the EDC, and in the case of an SAE, also 
on the formal reporting form designed to capture the required information. Reporting of these events 
will be in accordance with the rules around AE and SAE reporting described in the protocol, including 
notification of the IRB and/or FDA as required. 
8.4.4 
EVENTS OF SPECIAL INTEREST  
Of particular interest will be signs of systemic toxicity due to paclitaxel exposure; this is not expected 
and is considered unlikely given the mode of administration. Events of interest include systemic adverse 
effects known to be caused by paclitaxel e.g. neutropenia, febrile neutropenia, sepsis, anemia, 
thrombocytopenia, and peripheral neuropathy. Local AEs of interest include chest pain (pleuritic and 
non-pleuritic, back, shoulder), shortness of breath, cough, wheezing, hemoptysis, 
pneumonitis/pneumonia, mediastinitis, Superior Vena Cava (SVC) syndrome, Horner’s Syndrome, and 
bronchopleural fistula. 
8.4.5 
REPORTING OF PREGNANCY  
Female subjects must take a pregnancy test before receiving any treatment (Section 5.1 Participant 
Inclusion Criteria).  
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 Sponsor as soon as the Investigator is aware of it. The 
pregnancy will not be considered an SAE; however, information on these pregnancies will be collected 
and followed for the outcome of the pregnancy and the health of the newborn.  
Any pregnancy complication or premature terminations including miscarriage, spontaneous abortion, or 
elective termination of a pregnancy for medical reasons will be reported as an SAE, as described in 
Section 8.4.2. Should the pregnancy result in a congenital anomaly or birth defect, a separate SAE report 
must be submitted. Furthermore, all neonatal deaths that occur within 30 days of the birth should be 
reported as SAEs, without regard to causality. In addition, any infant death that occurs after the 30-day 
reporting period that the Investigator suspects is related to the in utero exposure to the study treatment 
should also be reported. 
8.5 
STUDY HALTING RULES  
This study is a Phase 2 study, and review of the safety and tolerability data will be conducted according 
to the schedule by the SRC. Following review, at any time point, the study may be terminated.  


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The study will be halted if there is any death, other than disease progression, which is at least possibly 
related to the study agent, or if two or more Grade 4 events which are at least possibly related to the 
study agent occur. 
Should the study be halted, all subjects who have received treatment will be followed to the completion 
of their participation to ensure all safety data is collected on all treated subjects. 
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 SRC. Membership of the SRC will constitute the 
Sponsor Medical Director, Principal Investigator, Medical Monitor, and an independent specialist 
physician (Section 8.1 Specification of Safety Parameters). 
All subject study data will be captured in an EDC system, allowing real-time access to ongoing safety and 
tolerability data.  
The SRC will convene to review the subject data, and a report will be generated outlining any safety 
concerns from the data available for review in the EDC.  Reviews will take place as described in Section 
6.1.7 and Section 8.1. 
During the SRC review, members will review all safety data as available in the EDC provided as reports 
generated directly from the EDC system and provided by the Data Management group. Particular 
emphasis will be placed on the events of special interest as outlined in Section 8.4.4 and on events 
which may constitute dose limiting toxicities as outlined in Sections 6.1.7 and 8.1. 
 
9 
CLINICAL MONITORING 
US Biotest monitors, or monitors designated by US Biotest, will conduct scheduled site visits to the 
investigational centers for the purposes of monitoring the study. The Investigator agrees to allow these 
monitors, and other authorized Sponsor personnel or designees, access to the subject’s medical records, 
regulatory binder, study binder, eCRFs, and source documents as needed to assure that the conduct of 
the study is within compliance.  
In addition, FDA or other government agencies may request an inspection following notification to the 
site. In such an event, the Investigator agrees to notify the Sponsor immediately of the request, and will 
allow Sponsor and inspectors to review records. 
US Biotest will conduct a site initiation visit to provide the Investigator and their staff with a 
comprehensive overview of the protocol and study procedures and to review mutual obligations and 
requirements of regulatory authorities. A regulatory file or binder containing required documentation 
will be kept at the site for reference and inspection. 


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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. 
10.2 
STATISTICAL HYPOTHESES 
No formal statistical inference (i.e., “p-values”) will be applied. The results of this trial will be based on 
descriptive statistics only. 
10.3 
ANALYSIS DATASETS 
In this safety and tolerability trial, all subjects who are enrolled and receive a dose of study agent will be 
included in the descriptive analysis.  
10.3.1 MISSING DATA 
Data will be presented as observed and no missing data imputation will be performed. All effort will be 
made to capture sufficient information to allow for medical interpretation of the results. 
The SAP will define intercurrent events (e.g.  not completing the full course of treatment (i.e. three 
injections), use of alternative medication, or stopping treatment due to an AE); different strategies will 
be developed to address the possible impact on the ability to derive a reliable treatment-related 
estimate of each of the outcomes of interest. 
Given the small number of subjects and the descriptive nature of summary statistics, it is recognized 
that looking at ‘sensitivity’ analyses will likely be limited to a variety of summary tables. 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
10.4.1 GENERAL APPROACH 
The focus of the trial will be on the safety and tolerability of the treatments. The general approach will 
be to highlight any trends that cause concern for the reviewing medical monitoring team (i.e., DLTs). 
Events that are related to the mode of administration will be presented separately from those that may 
have a relationship to the actual study medication. 


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10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Not applicable. The primary objective is to evaluate the safety and tolerability as demonstrated by AE, 
changes in laboratory assessments, physical examination findings and vital signs.  
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Secondary endpoints will be summarized descriptively. These will include supportive information to 
provide context for the dose(s) chosen to move forward for future study, as follows:  
• 
Concentration of paclitaxel in the systemic circulation post-injection (as determined by PK 
analysis); 
• 
Tumor response (RECIST as per Eisenhauer 2009); 
• 
Reduction in pain (as measured by the VAS). 
 
See also Section 10.4.11, Exploratory Analyses, for further details. 
10.4.4 SAFETY ANALYSES 
10.4.4.1 
ADVERSE EVENTS 
AEs recorded during the trial will capture medically relevant changes found during the physical exam, 
and medically relevant changes in vital signs and laboratory analytes found during the course of the trial. 
In addition, spontaneously reported or observed events will be recorded.  AEs will be recorded from Day 
1 to the Month 6 visit only. 
Events reported at or after the application of NanoPac will be considered TEAE. All reported events will 
be listed by subject number and cumulative dose to date, investigator term, Medical Dictionary for 
Regulatory Activities (MedDRA) coded term, date/study day (from initial treatment) for onset and 
cessation, severity (using the NCIC severity grading), and relationship to study medication. Only the TEAE 
will be tabulated.  
The primary safety analysis and clinical study report will be based on the data at the 3-month follow-up 
period. Additional tabulations including safety data up to and including the 6-month follow-up visit will 
also be presented. The focus of the summary will be on the cumulative dose just prior to the onset of the 
event for the subject. 
AE reports will be coded using the most recent version of MedDRA, signed off by the Medical Monitor, 
and presented by system organ class and preferred term. All AE and abnormal laboratory variables will 
be assessed according to the NCI-CTCAE v 5.0 grading system. The number of subjects reporting and 
number of events reported will be presented in frequency tables (overall, by intensity, by relationship 
and by outcome). AEs of special interest will be defined in the SAP and presented separately. The criteria 
for the most frequently reported events will be determined in the SAP after reviewing the data. 


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10.4.4.2 
LABORATORY ANALYTES 
Quantitative laboratory data will be summarized as mean values and change from screening scores (i.e., 
change = time point-screening) for each sampling time point. For tests with normal range provided, the 
clinical status and its change from screening (Normal/High Abnormal/Low Abnormal) will be 
summarized using shift tables. Analytes of particular interest (e.g., hematological tests) may be graphed 
by subject; these special analytes will be confirmed in the SAP. 
10.4.4.3 
VITAL SIGNS 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature and body weight) will be 
tabulated and mean raw values and changes from baseline scores (change = baseline-visit) where 
baseline is the last measurement prior to the study agent application, for each treatment group. 
10.4.4.4 
ECOG 
The ECOG scale will be tabulated as defined in the SAP using shift tables to summarize and highlight and 
changes in category across the visits. 
10.4.5 ADHERENCE AND RETENTION ANALYSES 
All subjects who enter the trial will be accounted for and any reasons for early termination noted – 
including disease progression.  
10.4.6  BASELINE DESCRIPTIVE STATISTICS 
Complete demographic and baseline data will be tabulated. The medical history, which will be coded in 
MedDRA, will be presented. The disease history data, with a focus on the previous treatment and 
current staging, and the information collected on the procedure to apply the treatment will also be 
summarized.  
10.4.7 PLANNED INTERIM ANALYSES  
• 
There are no formal interim analyses planned. There will be an ongoing safety and tolerability 
review by the Medical Monitor and regular SRC meetings between cohorts as outlined in Section 
8.  
10.4.7.1 
SAFETY REVIEW 
Safety Review is described in Section 8.1.  


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10.4.7.2 
EFFICACY REVIEW 
Imaging with CT scan will occur within four weeks prior to the injection procedure (, at Weeks 4, 8, 12, 
18, 24, 38, and 52, or at any time deemed to be required by the investigator.   
These results will be summarized and changes from the pre-dosing measurements highlighted. 
10.4.8 ADDITIONAL SUB-GROUP ANALYSES 
Subjects who perform particularly well (i.e., experience minimal AEs) may be compared to those who 
perform more poorly. This topic, and the criteria for defining each group, will be detailed in the SAP. 
10.4.9 MULTIPLE COMPARISON/MULTIPLICITY 
Not applicable, as no inferential analyses will be employed.  
10.4.10 TABULATION OF INDIVIDUAL RESPONSE DATA 
 
All data collected in the eCRF will at a minimum be listed; listings will support the tabulated 
data/outcomes.  
10.4.11 EXPLORATORY ANALYSES 
PK parameters (i.e., AUC, Cmax, Tmax) will be calculated based on the plasma concentration data for the 
first 24 hours. Concentration data collected at subsequent visits will be summarized separately. The 
method of summary will include tabulations by dose with any difference in the number of doses or 
cumulative dose, as outlined in the SAP and individual subject plots of concentration across time, if the 
data is amenable to these concepts. The final decision will be made after a review of the data and 
recorded in the SAP. 
Pain assessment scores will be summarized as mean values by dose across time as well as mean changes 
from baseline scores.  
QOL will be measured using the validated EQ-5D QOL instrument 
Flow cytometric analysis of blood samples and ICH evaluation of slides will be conducted by 
NeoGenomics (central laboratory) and they will be responsible for providing reports of these findings. 
These findings may be presented in a standalone report which will be integrated into the Clinical Study 
Report (CSR). 
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. 


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10.5 
SAMPLE SIZE 
Defining the primary endpoint explicitly requires understanding the primary purpose of the study. If, in 
this case, the primary purpose of the study is safety, then the incidence of DLTs would be an appropriate 
endpoint. When choosing events that will qualify as DLTs, it’s important to consider the rarity of events 
given the small number of subjects. For example, if a particular AE is known to occur in only 1% of 
subjects, there is an 16.5% chance it will appear in a particular cohort of 18 subjects. If the event only 
occurs in 5% of patients, there is only a 60.3% chance it will appear in a given 18-subject cohort, and for 
an event with a base occurrence rate of 10%, the probability of observing at least one event will be 85%. 
So, rarity is a factor that should be considered when deciding which adverse reactions to include as part 
of the endpoint. Estimates were obtained using the “confidence interval for probability of observing a 
rare event” calculation in nQuery Advisor version 8.3.   
10.6 
MEASURES TO MINIMIZE BIAS 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
Not applicable. 
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
Not applicable. 
10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
Not applicable.  
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
An eCRF is required and must be completed for each consenting and enrolled subject by qualified and 
authorized personnel. All data in the eCRF must reflect the corresponding source document. Any 
corrections to entries made on the eCRF must be documented in a valid audit trail. Only data required 
by the protocol for the purposes of the study should be collected within the EDC. 
The Investigator must maintain adequate and accurate source documents on which the eCRFs for each 
subject are based. They will be separate and distinct from the eCRFs. These records should include 
detailed notes on: 
• 
The medical history prior to the subject’s involvement in the study; 
• 
Date of informed consent; 
• 
The basic identifying information that links the subject’s medical record with the eCRFs; 
• 
The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject; 


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• 
The medical condition during the subject’s involvement in the study; 
• 
All AEs; 
• 
The subject’s exposure to the study medication; 
• 
The subject’s exposure to any concomitant therapy; 
• 
All relevant observations and data on the condition of the subject throughout the trial; 
• 
Justification for all entries in the subject’s eCRF.  
12 QUALITY ASSURANCE AND QUALITY CONTROL 
Data required by the protocol will be collected and entered into a validated data management system 
that is compliant with all regulatory requirements. The eCRF is an electronic document designed to 
record all of the protocol-required information to be reported to the Sponsor on each study subject. 
Data recording must follow the instructions described in the CRF Completion Guidelines. The PI has 
ultimate responsibility for the collection and reporting of all clinical data entered on the eCRF. The PI or 
designee, as identified on Form FDA 1572, must electronically sign the completed eCRF for each 
participating subject to attest to its accuracy, authenticity, and completeness. 
The EDC application being used in this study is TrialMaster® version 4.2.1 from OmniComm Systems. 
TrialMaster studies are hosted from a state-of-the-art data center with rigorous physical and electronic 
security. All data is backed up daily to Iron Mountain, in Ohio and is also backed up to a hurricane-proof 
bunker in Fort Lauderdale, Florida. OmniComm has achieved certification with European “Safe Harbor” 
regulations, meaning that all necessary measures are in place to protect patient confidentiality even 
with the data being stored in a US data center. The data management and statistical CRO, McDougall 
Scientific Ltd., ensures that the development of the eCRF follows their SOPs which are based on the 
Systems Development Life Cycle (SDLC) methodology. Access to the system is restricted by username 
and password; these are controlled by the Data Management CRO. All personnel using the system will 
be trained and the training documented. All changes to the database are recorded in an audit trail. The 
database will be locked when all outstanding queries have been addressed, all agreed-to data is marked 
as source-verified, and the PI has signed off on the eCRF contents.  
All software applications used in the collection of data will be properly validated following standard 
computer system validation that is compliant with all regulatory requirements.  
13 ETHICS/PROTECTION OF HUMAN SUBJECTS  
 
13.1 
ETHICAL STANDARD  
The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki. 
Sponsor and Investigator will comply with their responsibilities as defined in 21 CFR 312.50-312.70. 


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13.2 
INSTITUTIONAL REVIEW BOARD  
Before the start of the study, the study protocol, informed consent form and/or other appropriate 
documents will be submitted to the IRB and/or the authorities in accordance with local legal 
requirements. It is the responsibility of the Investigator to assure that all aspects of the IRB review are 
conducted in accordance with current regulations. US Biotest and the Investigator must inform each 
other in writing that all ethical and legal requirements have been met before the first subject is enrolled 
in the study. 
Amendments to the protocol will be subject to the same requirements as the original protocol. All 
changes to the consent form will be IRB-approved; a determination will be made regarding whether 
previously consented participants need to be re-consented. 
13.3 
INFORMED CONSENT PROCESS  
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
Subjects being considered for participation in this study will be provided an informed consent form (ICF) 
to read and sign before being permitted to participate. The ICF will describe the study agent and any 
prior findings from previous studies; study procedures including the timing of study clinic visits and their 
responsibilities to adhere to those timelines; any risks which may be associated with the study agent or 
the procedures being carried out in the study; and all other items required under 21 CFR Part 50.25.  
Subjects will be required to provide signed consent prior to the conduct of any study-related 
procedures. The Investigator is required to document the process for obtaining informed consent in the 
source notes. 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
The Investigator will obtain informed consent from each subject enrolled in the study, in accordance 
with the U.S. Food and Drug Administration (FDA) regulations 21 CFR 50.20 - 50.27 and the laws and 
regulations of the state in which the investigation is being conducted. The IRB must approve the ICF to 
be used by the Investigator. The Investigator will provide the Sponsor with a copy of the written 
approval generated by the IRB or Ethics Committee before the Investigator will be permitted to enroll 
subjects into the study. 
It is the responsibility of the Investigator to ensure that informed consent is obtained from the subject 
or his/her guardian or legal representative before any activity or treatment is undertaken which is not 
part of routine care. This includes, but is not limited to, the performance of diagnostic or therapeutic 
procedures and the administration of study agent. The draft version of the informed consent document 
will be modified by each site and reviewed and approved in writing by US Biotest prior to submission to 
the IRB. 


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Should a protocol amendment be made, the subject consent form may be revised to reflect the changes 
of the protocol. If the consent form is revised, it is the responsibility of the Investigator to ensure that an 
amended consent is approved by the IRB and signed by all subjects currently on study, as well as those 
subsequently entered in the study. 
The Investigator will not undertake any investigation specifically required only for the clinical study until 
valid consent has been obtained. The terms of the consent and when it was obtained must also be 
documented in the eCRF. The original, signed informed consent document must be maintained on file at 
the study site and be made available for review during monitoring visits and site audits. 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
All local legal requirements regarding data protection will be enforced. All study findings and documents 
will be regarded as confidential. The Investigator and members of his/her research team must not 
disclose such information without prior written approval from US Biotest.  
The anonymity of participating subjects must be maintained to the extent required by law. Throughout 
documentation and evaluation, the subjects will be identified on eCRFs and other documents submitted 
to US Biotest by their initials, birth date, and subject number. The subjects will be told that all study 
findings will be stored and handled in strictest confidence, according to legal requirements, and that 
authorized research Investigators and agents of the FDA, the NCI, and authorized personnel of US 
Biotest have the right to inspect their medical records. 
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
Samples and data collected under this protocol are specifically for use in the evaluation and analyses 
being conducted in the study. Samples will not be available for purposes other than indicated within this 
protocol. No genetic testing will be performed. 
Access to stored samples will be limited to personnel authorized to have access at the site prior to 
shipping to the laboratories for analysis/assessment. Samples will be stored using codes assigned by the 
Sponsor or as required by the clinical laboratories.  
Samples will only be retained until analysis is complete, after which they will be disposed of according to 
the laboratory SOPs. No samples will be retained for any future use. 
Data will be kept in password-protected computers. Only Investigators and those delegated 
responsibility on the Delegation of Authority Log will have access to the samples and data. 
Copies of imaging data provided to the Sponsor will be filed in a secure cabinet with controlled access 
and held for review until archiving of the study documents, at which time the redacted imaging data will 
be archived together with the Trial Master Filed. 


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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 data is ALCOA-C compliant.  
For electronic source, the institution must provide a secure, validated electronic medical record (EMR) 
data management system that is 21 CFR Part 11 compliant and meets all regulatory requirements, 
regulations and quality standards.  
For paper source, documentation is expected to be completed in a neat, legible manner to ensure 
accurate interpretation of data. Black or blue ink is required to ensure clarity of reproduced copies.  
Source documents will be maintained for recording data for each participant enrolled in the study. Data 
reported in the eCRF derived from source documents should be consistent with the source documents. 
Any discrepancies should be explained and captured in a progress note and maintained in the subject’s 
official electronic study record. 
The EDC application being used in this study is TrialMaster® version 4.2.1 from OmniComm Systems. 
TrialMaster studies are hosted from a state-of-the-art data center with rigorous physical and electronic 
security. All data is backed up daily to Iron Mountain, in Ohio and is also backed up to a hurricane-proof 
bunker in Fort Lauderdale, Florida. OmniComm has achieved certification with European “Safe Harbor” 
regulations, meaning that all necessary measures are in place to protect patient confidentiality even 
with the data being stored in a US data center. The data management and statistical CRO, McDougall 
Scientific Ltd., ensures that the development of the eCRF follows their SOPs which are based on the 
Systems Development Life Cycle (SDLC) methodology. Access to the system is restricted by username 
and password; these are controlled by the Data Management CRO. All personnel using the system will 
be trained and the training documented. All changes to the database are recorded in an audit trail. The 
database will be locked when all outstanding queries have been addressed, all agreed-to data is marked 
as source-verified, and the PI has signed off on the eCRF contents.  
Data recording must follow the instructions described in the eCRF Completion Guidelines. The PI has 
ultimate responsibility for the collection and reporting of all clinical data entered on the eCRF. The PI or 
designee, as identified on the Delegation of Responsibilities Log (and included on Form FDA 1572), must 
electronically sign the completed eCRF to attest to the accuracy, authenticity, and completeness of the 
data. 
The database will be locked when all outstanding queries have been addressed, all agreed-to data is 
marked as source-verified, and the PI has signed off on the eCRF contents. 


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14.2 
STUDY RECORDS RETENTION  
The Investigator must retain a copy of all study documents in accordance with FDA or local regulations, 
whichever are the more stringent. 
The Investigator must maintain study documents: 
• 
For a minimum of two years following the date the marketing application (NDA) is approved for the 
indication for which the drug was investigated;  
• 
For a minimum of two years following the release date of the final report, if no marketing 
application is to be filed, or if the marketing application is not approved for the indication of which 
the drug was investigated or is discontinued and FDA has been notified; or, 
• 
For a minimum of 15 years after the completion or discontinuation of the study to be filed in 
support of the registration in the European Union. 
If the Investigator relocates, retires or withdraws from the study for any reason, the study records may 
be transferred to an acceptable designee, such as another Investigator, another institution, or the 
Sponsor. The Investigator must obtain the Sponsor’s written permission before transferring or disposing 
of any records. 
14.3 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice (GCP), or 
FDA or IRB requirements. The noncompliance may be either on the part of the participant, the 
Investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by 
the site and implemented promptly. 
These practices are consistent with ICH E6:  
• 
4.5:  Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1:  Quality Assurance and Quality Control, Section 5.1.1  
• 
5.20:  Noncompliance, Sections 5.20.1, and 5.20.2.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations as soon as 
possible after occurrence and identification of the protocol deviation. All deviations must be addressed 
in study source documents, and reported to the Sponsor and the Data Management group.  
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to IRB requirements.  
Serious non-compliance on the part of the site, and an inability of the Sponsor to bring the site back into 
compliance, will be reported to FDA in accordance with their requirements.  


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14.4 
PUBLICATION AND DATA SHARING POLICY 
By signing the study protocol, the Investigator agrees with the use of results of the study for the 
purposes of national and international registration, publication, and information for medical and 
pharmaceutical professionals. If necessary, the authorities will be notified of the Investigator's name, 
address, qualifications, and extent of involvement. The Sponsor will prepare an integrated 
clinical/statistical report. Publication/presentation of data is not allowed without explicit permission 
from US Biotest, Inc. Submission of data for publication/presentation will be coordinated and approved 
by US Biotest in collaboration with the Investigator. 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a 
clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any 
research project that prospectively assigns human subjects to intervention or concurrent comparison or 
control groups to study the cause-and-effect relationship between a medical intervention and a health 
outcome. Medical interventions include drugs, surgical procedures, devices, behavioral treatments, 
process-of-care changes, and the like. Health outcomes include any biomedical or health-related 
measures obtained in subjects or participants, including PK measures and AE. The ICMJE policy, and the 
Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that all clinical 
trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the National 
Library of Medicine. Data entered to the ClinicalTrials.gov website will be in accordance with FDA 
requirements for this registration and for publication of study results on that site. 
15 STUDY ADMINISTRATION 
 
15.1 
STUDY LEADERSHIP 
The study will be overseen by the Study Manager who will be responsible, together with the 
Investigators, for tracking enrollment, timelines, and deliverables, and other study-related performance. 
All questions regarding the enrollment of subjects, regulatory requirements for the conduct of the 
study, safety reporting, or study conduct should be addressed to the Study Manager or Site Monitor 
designated by the Sponsor. Contact information for the Sponsor is provided near the beginning of this 
protocol and a full Sponsor study team list will be provided to the Investigator in separate study 
documents. 
16 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical and therefore any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial. As required by FDA, a Financial Disclosure Form 


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will be completed by each person noted on the FDA Form 1572 for this study at the site, the original will 
be filed in the TMF, and a copy will remain in the site’s regulatory binder. 
17  LIABILITY AND INSURANCE  
The Sponsor will take out reasonable third-party liability insurance coverage in accordance with all local 
legal requirements. This insurance will cover all parties involved in the trial including, but not necessarily 
limited to, the principal investigator, clinical trial site, and subjects.  
 
 


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18  LITERATURE REFERENCES  
 
ABRAXANE Package Insert. Celgene Company. Rev July 2015. 
 
Ҫelikoğu SI, Karayel T, Demirci S, Ҫelikoğu F, Cagatay T. Direct Injection of Anti-Cancer Drugs into 
Endobronchial Tumors for Palliation of Major Airway Obstruction. Postgrad Med J 1997; 73: 159-162. 
 
Celikoglu F, Celikoglu SI, York AM, Golberg EP. Intratumoral administration of cisplatin through a 
bronchoscope followed by irradiation for treatment of inoperable non-small cell obstructive lung cancer. 
Lung Cancer. 2006 Feb;51(2):225-36. Epub 2005 Dec 15. 
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
Lu B, Sun L, Yan X, Ai Z, Xu J. Intratumoral chemotherapy with paclitaxel liposome combined with 
systemic chemotherapy: a new method of neoadjuvant chemotherapy for stage III unresectable non-
small cell lung cancer. Med Oncol. 2015 Jan;32(1):345. doi: 10.1007/s12032-014-0345-5. Epub 2014 Nov 
28. 
 
Mehta HJ, Begnaud A, Penley AM, Wynne J, Malhotra P, Fernandez-Bussy S, Cope J, Shuster JJ, Jantz MA. 
Restoration of Patency to Central Airways Occluded by Malignant Endobronchial Tumors Using 
Intratumoral Injection of Cisplatin. Ann Am Thorac Soc Vol 12, No 9, pp 1345–1350, Sep 2015. 
 
Mehta, H.J., Jantz, M.A. Endobronchial Ultrasound-guided Intratumoral Injection of Cisplatin for the 
Treatment of Isolated Mediastinal Recurrence of Lung Cancer. J. Vis. Exp. (120), e54855, 
doi:10.3791/54855 (2017). 
 
Taxol® (paclitaxel) Injection Package Insert. Bristol-Myers Squibb Company. Rev July 2011. 
 
Williamson SK, Johnson GA, Maulhardt HA, Moore KM, McMeekin DS, Schulz TK, et al. A phase I study of 
intraperitoneal nanoparticulate paclitaxel (Nanotax®) in patients with peritoneal malignancies. Cancer 
Chemother Pharmacol. 2015 May;75(5):1075-1087. 
 
Yarmus L, Mallow C, Akulian J, Ting Lin C, Ettinger D, Hales R, Rahn Voong K, Lee H, Feller-Kopman D, 
Semaan R, Seward K, Wahidi MM.  Prospective Multicentered Safety and Feasibility Pilot for 
Endobronchial Intratumoral Chemotherapy.  Chest 2019; 156 (3): 562-570.  
 


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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: 
Confidential & Proprietary
Statistical Analysis Plan 
Protocol #:
NANOPAC-2020-01
Protocol Title:
Phase 2 Trial Evaluating the Safety and Tolerability of Intratumoral 
Injections of NanoPac® with Standard of Care Therapy in Subjects with 
Lung Cancer
Project Code:
NA09NAJ
Study Phase:
2
Trial Design:
Open-label, single arm, safety/tolerability focus
Study Drugs:
NanoPac (Sterile Nanoparticulate Paclitaxel) Powder for Suspension at 15 
mg/mL concentration in intratumoral injection of up to 20% of the total 
calculated tumor and lymph node volume
Patients:
18
Treatment Period:
12 weeks (plus 40 weeks follow-up)
Sponsor Contact:
Shelagh Verco, PhD
US Biotest, Inc.
231 Bonetti Dr., Suite 240, San Luis Obispo, CA
93401-7301, USA
(805) 704-1179
Shelagh.verco@usbiotest.com
Analysis Contact:
Xuecheng Liu, PhD
Alimentiv Inc.
789 Don Mills Rd, Suite 802
Toronto, Ontario, M3C 1T5
xuecheng.liu@alimentiv.com
Date:
November 13, 2023
Status:
Final


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Signature Approval Page
1 of 2
Date of Final Protocol:
07-Jul-2021 v4.0
Amendments:
20-Mar-2020 v2.0
13-Nov-2020 v3.0
07-Jul-2021 v4.0
Date of Final Plan
13-Nov-2023
I have reviewed the Statistical Analysis Plan. My signature below confirms my agreement with 
the contents and intent of this document.
Author:
Xuecheng Liu, PhD
Statistician
Alimentiv Inc.
Reviewed by:
Chungui Wang 
Senior Statistician 
Alimentiv Inc. 


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Signature Approval Page
2 of 2
Date of Final Protocol:
07-Jul-2021 v4.0
Amendments:
20-Mar-2020 v2.0
13-Nov-2020 v3.0
07-Jul-2021 v4.0
Date of Final Plan
13-Nov-2023
I have reviewed the Statistical Analysis Plan.  My signature below confirms my agreement with 
the contents and intent of this document.
Reviewed by:
Shelagh Verco, PhD
VP, Clinical Development, 
US Biotest, Inc.
Gere diZerega, MD 
President and CEO 
US Biotest, Inc. 


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Contents 
List of Abbreviations and Definition of Terms ............................................................................. 3 
Definition of Term(s)................................................................................................................... 4 
1 
Background .................................................................................................................... 5 
2 
Objectives ...................................................................................................................... 5 
2.1 
Primary Objective ................................................................................................ 5 
2.2 
Secondary Objectives......................................................................................... 5 
2.3 
Exploratory Objectives ....................................................................................... 6 
3 
Study Design.................................................................................................................. 6 
3.1 
Primary Outcomes .............................................................................................. 7 
3.2 
Secondary Outcomes ......................................................................................... 7 
3.3 
Exploratory Outcomes ........................................................................................ 8 
3.4 
Pharmacokinetic/Pharmacodynamic/Pharmacoeconomic Outcome(s) ..... 8 
4 
Data Management.......................................................................................................... 8 
4.1 
Data Management............................................................................................... 8 
4.2 
Coding ................................................................................................................... 9 
4.3 
Pharmacokinetics (PK) Data ............................................................................. 9 
4.4 
Flow Cytometry and Immunohistochemistry ................................................... 9 
4.5 
Missing Data ........................................................................................................ 9 
5 
Change to Analysis as Outlined in the Protocol .............................................................. 9 
6 
Statistical Methods ........................................................................................................10 
6.1 
Calculated Outcomes ....................................................................................... 10 
6.2 
Analysis Population........................................................................................... 12 
6.3 
Analysis Methods .............................................................................................. 12 
7 
RESULTS......................................................................................................................13 
7.1 
Study Subjects ................................................................................................... 13 
7.1.1 
Subject disposition .................................................................................13 
7.1.2 
Demographics and Baseline Characteristics ..........................................13 


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7.1.3
Lung Cancer History...............................................................................13
7.1.4 
History of IV Chemotherapy/Radiotherapy/Targeted Therapy Regimens13 
7.1.5 
Medical History.......................................................................................13 
7.1.6 
NanoPac Administration.........................................................................14 
7.2 
Primary Outcomes ............................................................................................ 14 
7.2.1 
Adverse Events ......................................................................................14 
7.2.2 
Laboratory Assessments........................................................................14 
7.2.3 
Physical Examination .............................................................................15 
7.2.4 
Vital Signs and Body Measurements......................................................15 
7.3 
Secondary Outcomes ....................................................................................... 15 
7.3.1 
Paclitaxel Concentration and Presence ..................................................15 
7.3.2 
Overall and Progression-Free Survival ...................................................16 
7.3.3 
Tumor Measurement and Response ......................................................16 
7.4 
Exploratory Outcomes ...................................................................................... 16 
7.4.1 
Eastern Cooperative Oncology Group (ECOG) Scores ..........................16 
7.4.2 
Pain........................................................................................................16 
7.4.3 
Quality of Life .........................................................................................16 
7.4.4 
Flow Cytometry (FCM) and Multiplexed immunofluorescense (mIF).......17 
7.5 
Others ................................................................................................................. 17 
7.5.1 
Concomitant Medication.........................................................................17 
7.5.2 
Concomitant Procedures........................................................................17 
7.5.3 
Concomitant IV Chemotherapy/Radiotherapy/Targeted Therapy Regimen
...............................................................................................................17 
References ...............................................................................................................................17 


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List of Abbreviations and Definition of Terms
Abbreviation or Term
Definition
AE
Adverse Event
AESI
Adverse Event of Special Interest
APR
Analysis Programming Requirements - detailed programming 
specifications required to convert the CRF data into 
analysis/presentation data sets.
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
CT
Computerized Tomography
DLT
Dose Limiting Toxicity
DMP
Data Management Plan
EBUS-TBNI
Endobronchial Ultrasound-Guided Transbronchial Needle Injection
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
FCM
Flow Cytometry
IP
Intraperitoneal
ITU
Intratumoral
MedDRA
Medical Dictionary for Regulatory Activities (coding for AEs)
mIF
multiplex Immunofluorescense
NSCLC
Non-small Cell Lung Cancer
OS
Overall Survival
PCHG
Percentage of Change
PFS
Progression-Free Survival
PK
Pharmacokinetics
QOL
Quality of Life
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCLC
Small Cell Lung Cancer
SDLC
Systems Development Lifecycle
SOC
System Organ Class
SoC
Standard of Care
SOP
Standard Operating Procedure
SRC
Safety Review Committee
TEAEs
Treatment Emergent Adverse Events
VAS
Visual Analogue Scale
WHO
World Health Organization


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Abbreviation or Term
Definition
WHODD
World Health Organization Drug Dictionary
Definition of Term(s)
Term
Definition
NanoPac
Sterile Nanoparticulate Paclitaxel. The investigational product. 


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1
Background
NANOPAC-2020-01 is a Phase 2, open-label trial in 18 subjects with lung cancer. Subjects will 
be given intratumoral (ITU) NanoPac injections via endobronchial ultrasound-guided 
transbronchial needle injection (EBUS-TBNI) directly into the lung cancer lesions and metastatic 
lymph nodes on up to three separate occasions 4 weeks apart. 
This trial is designed to primarily evaluate the safety and tolerability of NanoPac injections, with 
secondary investigations of the pharmacokinetics of NanoPac, subject progression-free and 
overall survival, and lesion response to treatment. 
There have not been previous clinical trials with NanoPac in the lung, but some previous clinical 
trials with NanoPac were have been completed. 
A Study in Prostate Cancer with direct injection of NanoPac into the prostate appears 
safe and tolerable. 
A Study in Peritoneal Malignancies with intraperitoneal (IP) NanoPac did not lead to 
increases in systemic toxicity over that usually associated with IV paclitaxel. 
A study in ovarian cancer with NanoPac direct instillation into the peritoneum just prior to 
surgical cytoreductive close shows, overall, a 66% progression-free survival (PFS) 
occurred at 12 months post-IP NanoPac, with further improvement noted at 18 months 
after treatment, supported by sustained reduction in cancer antigen 125 (CA-125) and 
lack of additional cancer-related symptoms 6 months or more after treatment.  
A Study in Pancreatic Mucinous Cystic Neoplasms shows that, there was no apparent 
association of the number, severity, or relationship of treatment emergent adverse 
events (TEAEs) with the dose/concentration or number of injections administered. 
Analysis of the response rate of subjects demonstrated that the majority of subjects 
demonstrated stabilization or improvement in calculated volume and/or longest diameter 
of the cyst.
2
Objectives
2.1
Primary Objective
The primary objective of this study is to evaluate the safety and tolerability of NanoPac injected 
directly into lung cancer lesions and metastatic lymph nodes by EBUS-TBNI on multiple (up to 
three) occasions, each injection procedure administered 4 weeks apart. Safety and tolerability 
will be assessed for 24 weeks following first NanoPac injection; with additional follow-up at 
weeks 38 and 52. 
2.2
Secondary Objectives
a) To describe the PK of NanoPac when administered into the tumor(s) within the lung;
b) To evaluate effect on progression-free survival (PFS) and overall survival (OS) in this 
population; and


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c) to assess changes in the treated lesion (and lymph nodes) via CT scan imaging.
2.3
Exploratory Objectives
a) To assess the changes in Eastern Cooperative Oncology Group (ECOG) Performance
Status;
b) To assess the changes in pain (as measured by the visual analog scale [VAS]);
c) To assess the changes in QOL as measured by the validated EQ-5D QOL instrument, and
d) To assess the changes in immune markers in the blood by flow cytometry, and in the tissue 
by multiplex immunofluorescense (mIF).
3
Study Design
In this open-label, Phase 2, single arm trial, subjects with lung cancer will be receiving or plan to 
receive standard of care (SoC) treatment and will be enrolled after confirmation of adequate 
hematologic function. 
Subjects will receive NanoPac via EBUS-TBNI to up to two lung lesions and up to five 
associated lymph 
Subjects will be followed for safety during the 24 weeks following first NanoPac injection. 
The population in this trial consists of 18 subjects with primary or recurrent non-resectable non-
small cell lung cancer (NSCLC) or small cell lung cancer (SCLC), with primary or recurrent 
measurable disease limited to the tracheal, hilar, mediastinal, and peribronchial structures (lung 
tumors and lymph nodes) accessible through EBUS-TBNI.
Subjects will be enrolled to receive up to three injection procedures with 15 mg/mL NanoPac, 
each injection 4 weeks apart, in up to two parenchymal lung lesions and associated 
local/regional lymph nodes, up to a maximum of 20% of the tumor and lymph node volume, 
individually and/or in total. A maximum of 40 mL of NanoPac will be injected in one procedure. If 
more than one lesion is present in the lung and more than one lesion is planned to be treated, 
the Investigator will select a primary or target lesion. Depending on the amount of NanoPac 
used for injection of the primary/target lesion, the remaining NanoPac may be administered into 
a second lung tumor lesion and/or metastatic lymph nodes up to a maximum volume of 40 mL 
of NanoPac.
Subjects will be followed for signs of preliminary efficacy by assessment of tumor response 
classified according to RECIST 1.1 criteria, with tumor size assessed by CT imaging at baseline 
(Screening), prior to each injection, and at Weeks 12, 18, 24, 38, and 52. Subjects will also be 
assessed for quality of life (QOL) changes using the EQ-5D QOL questionnaire, PFS and OS
See the study schedule below for details of visit information.


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3.1
Primary Outcomes
The primary outcomes will be safety and tolerability, as assessed by adverse events (AEs),
changes in vital signs, laboratory results, and changes in physical examination following 
NanoPac injection up to Week 24.
3.2
Secondary Outcomes
Concentration of paclitaxel in the systemic circulation post-injection, as determined by 
PK analysis. Additionally, presence of paclitaxel in tissue biopsy samples obtained prior 
to each NanoPac injection;
PFS (as assessed using RECIST v1.1) and OS to Week 52. Week 24 PFS and OS are a 
point of focus;


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Changes in all tumor and lymph node dimensions and volume, as determined by CT 
scan imaging, at Weeks 12, 24, 38, and 52 compared to baseline. Any changes in 
characteristics of tumors/nodes as determined by CT scan. 
3.3
Exploratory Outcomes
Change in Eastern Cooperative Oncology Group (ECOG) Performance Status at Weeks 
12 and 24 from baseline;
Changes in pain as measured by visual analog scale (VAS) at post-baseline visits up to 
Week 24 compared to baseline;
Changes in Quality of Life (QOL) as measured by the EQ-5D Quality of Life Scale at 
Weeks 4, 8, 12, 18, 24, 38, and 52, compared to baseline;
Immune markers assessed in the blood by flow cytometry (FCM), and in the tissues via 
multiplexed immunofluorescense (mIF).
3.4
Pharmacokinetic/Pharmacodynamic/Pharmacoeconomic Outcome(s)
Concentration of paclitaxel in the systemic circulation;
Concentration of paclitaxel in tissue biopsy samples.
4
Data Management
4.1
Data Management
Most data will be collected at the sites via an electronic data capture (EDC) system.  The study-
specific application will be developed based on the protocol requirements and following the full 
Systems Development Lifecycle (SDLC). The development and management of the trial 
application, including security and account administration, will adhere to the Standard Operating 
Procedures (SOPs) at Alimentiv.  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.


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External laboratory data (from PK analysis, flow cytometry, and mIF) will not be entered into EDC 
system. External data sets will be provided.
The data management processes are outlined in the project specific Data Management Plan 
(DMP); this and all related documentation are on file at Alimentiv Inc. and are identified by the 
project code NA09NAJ.
All programming will be performed in SAS EG 8.2.
4.2
Coding
AEs and medical history will be coded in MedDRA version 23.1 and signed off by US Biotest, 
Inc. The coding will be reviewed and signed off prior to database lock.  All concomitant 
medications will be coded using the WHO Drug Dictionary (WHODD) Version March 1, 2020.
4.3
Pharmacokinetics (PK) Data
PK Data will be provided to Alimentiv in Excel data sheets to be transferred into the SAS system 
for summary and listings. Analyses will be performed by an external expert and will be reported 
separately.
4.4
Flow Cytometry and Immunohistochemistry
Analysis of whole blood FCM and biopsy mIF will be performed by NeoGenomics Laboratories, 
Inc. The results will be provided to Alimentiv in Excel data sheets to be transferred into the SAS 
system for listings.
4.5
Missing Data
Given that the primary objective of this study is to evaluate the safety and tolerability, there will 
not be any missing data imputation or sensitivity analyses.
In addition, since the primary objective of this study is to evaluate the safety and tolerability, for 
all possible intercurrent events (e.g. not completing the full course of treatment (i.e. three 
injections), use of alternative medication, stopping treatment due to an AE, or death), analyses 
of the outcomes will follow a treatment policy strategy: that means, any data collected, whether 
from prior to or after the intercurrent event, will be summarized without modification due to any 
intercurrent events. 
5
Change to Analysis as Outlined in the Protocol
Section 10.4.11 of the protocol specifies that PK parameters (AUC, Cmax, Tmax) will be 
calculated based on plasma concentration data for the first 24 hours. The protocol specifies PK 
plasma draws prior to injection and at 1, 2 and 4 hours post-injection; these are not sufficient to 
calculate AUC, Cmax, and Tmax, within an acceptable degree of accuracy and so PK 
parameters are not included in the SAP.


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6
Statistical Methods
6.1
Calculated Outcomes
The following are key outcomes derived from data captured in the EDC.  Complete 
documentation of the calculations and data manipulation required to go from EDC to the 
analysis database are contained in the companion document - the study Analysis Programming
Requirements (APR).
Age: It is defined as informed consent year 
birthdate year, if consent date was on or after 
birthday, or as informed consent year 
birthdate year 
1, if consent date was before birthday. 
Study day: Study day is defined as date of event (or assessment) - first NanoPac injection date 
+ 1, if the date is on or after the first NanoPac injection; it is defined as date of event (or 
assessment) - first injection date, if the date is before the first NanoPac injection. 
(The study day of first NanoPac injection day is 1, i.e., Day 1.)
Baseline: The baseline value of a measurement is defined as the last non-missing 
measurement prior to NanoPac injection on Day 1. 
Change from Baseline: Value collected at time point (Visit) 
Baseline value. 
Time on Treatment (days): Date of last NanoPac injection 
Date of first NanoPac injection + 
1. (That is the study day of the last NanoPac injection.)
Time in Trial (days): Week 52 visit date or withdrawal date (whichever is smaller) 
informed 
consent date + 1.
Body Mass Index (BMI): The ratio of weight (in kg) at the visit and square of the height (in 
meter) at the screening.  
Treatment Emergent Adverse Event (TEAE): It is 
Cumulative Dose numbers: Dose numbers received just prior to the onset of AE.
AE of special interest (AESI): As described in protocol Section 8.4.4, events of interest in 
MedDRA preferred terms include
Acute interstitial pneumonitis;
Anaemia;
Bronchial obstruction;
Bronchitis;
Bronchospasm;
Chest discomfort;
Cough (only reported term Worsening cough
);
Dyspnoea;


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Febrile neutropenia;
Haemoptysis;
Hypoxia;
Musculoskeletal chest pain;
Pleural effusion;
Pneumonia;
Pneumonia pseudomonal;
Pneumonitis;
Collapse of lung (in low level term);
Productive cough (only reported terms
Pulmonary embolism;
Tachypnoea.
Local AE of interest: As described in protocol Section 8.4.4, local adverse events of interest in 
MedDRA preferred terms include:
Acute interstitial pneumonitis;
Bronchial obstruction;
Bronchospasm;
Cough;
Haemoptysis;
Pneumonia (only reported terms Infection (pneumonia)
Pneumonia
included);
Pneumonitis;
Productive cough (only reported terms
Pulmonary embolism
Tumor Volume: For a tumor or a lymph node, its volume is defined as
(1/6)*3.1416*(diameter 1)* (diameter 2)* (diameter 3) if 3 diameters are available; 
(1/6)*3.1416*(diameter 1)* (diameter 1)* (diameter 2) if only two diameters are available, 
and (by convention,) diameter 1 is longer than or equals to diameter 2;
(1/6)*3.1416*(diameter 1)* (diameter 1)* (diameter 1) if only one diameter is available.  
Response Evaluation of A Target Lesion Based on Longest Diameter (RECIST 1.1):
Calculating the percentage of change (PCHG) from baseline in longest diameter of the lesion, 
the response is 
"Complete Response (CR)" if PCHG = -100; 
"Partial Response (PR)" if -100 < PCHG 
-30; 
"Stable Disease (SD)" if -30 < PCHG < 20; 
"Progressive Disease (PD)" If PCHG
20.


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Response Evaluation of a Target Lesion Based on Volume (and based on RECIST 1.1),
Calculating PCHG in the volume of the lesion, the response is defined as the same way as in 
PCHG for longest diameter.
Progression (Yes/No)
Stable Disease (SD).
Progression-Free Survival (PFS): It is the time from the first injection date to the date of 
progression or death, which equals the study day the date of progression or death. Unless an 
exact date is noted, when progression occurs noted at a visit, the PFS is the study day of the 
last visit among progression-free visits. In the case of no progression recorded, PFS is right
censored at the end of study date or the early withdraw date.
Overall Survival (OS): In the case of death, the time is defined as the study day of the date of 
death. Otherwise, it is right censored at the end of study date or the early withdraw date.
6.2
Analysis Population
Safety population: Safety population consists of all subjects who receive at least one
NanoPac injection. Safety population is the analysis population for all outcomes. 
Efficacy population: Efficacy population consists of all subjects in safety population with lung 
cancer.    
Cohorts: Three cohorts will be defined according to the total numbers of doses patients 
received.     
Additional sub-group analysis: The following three sub-group variables will be used in sub-
group analyses:
Category of Non-Small Cell Lung Cancer (NSCLC): Squamous Cell Carcinoma (SCC) 
SCC, or Adenocarcinoma (AC) 
Dichotomized the sum of numbers of tumors and of lymph nodes in the screening visit
into two categories: 1 or 2  tumors/nodes and more than 2 tumors/nodes.
Dichotomized the size of tumors injected at medium (50% to 50%, or as close as 
possible) and named as small tumor size and large tumor size. (Note that the size of a
tumor is the longest diameter of the primary tumor.)   
6.3
Analysis Methods
All calculations and analyses (including analyses for OS and PFS) will be performed using SAS 
EG 8.2. Continuous data will be summarized via mean, standard deviation, median, range, and 
95% confidence intervals, while categorical data will be presented as counters and 
percentages/proportions. 
No statistical inference will be made for any outcomes.


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Protocol Number: NANOPAC-2020-01
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7
RESULTS
All data collected in the EDC will be at a minimum listed. The eligibility data will be provided in a 
separate listing(s).
Summaries will be conducted by the 3 cohorts. Additional sub-group analyses will be conducted 
with the 4 sub-group variables.
7.1
Study Subjects
All baseline data will be analyzed based on safety population.
7.1.1
Subject disposition
All enrolled and treated subjects will be accounted for. All early discontinuations will be 
summarized by primary reason for discontinuation. Days in treatment, days in trial, survival 
days, days from diagnosis to first injection, and days from first injection to death will also be 
summarized. 
Sub-groups, date of informed consent, date of each treatment, date of end of study, days in 
treatment and days in study, reason for early discontinuation will be listed.
Date of (lung cancer) disease diagnosis, date of death, days from diagnosis to screening, to first 
injection, and to death will be listed.   
7.1.2
Demographics and Baseline Characteristics
Demographics (age, sex, ethnicity, and race), baseline body measurements (height, weight, and 
calculated BMI), and vital signs (systolic and diastolic blood pressure, heart rate, and 
temperature) will be summarized and listed.
7.1.3
Lung Cancer History
Lung cancer history (including stage of lung cancer (if available); histological type (squamous, 
adenocarcinoma) and initial diagnosis date will be listed.
7.1.4
History of IV Chemotherapy/Radiotherapy/Targeted Therapy Regimens
History of IV Chemotherapy/Radiotherapy/Targeted Therapy Regimens (including number of 
cycles planned and number of cycles completed and frequency) will be listed.
7.1.5
Medical History
Medical history (other than lung cancer history and history of IV Chemotherapy/ Radiotherapy/ 
Targeted Therapy Regimens) will be listed and be summarized by MedDRA System Organ 
Class and by Preferred Term.


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7.1.6
NanoPac Administration
NanoPac administration from all injection days, including injection date, time, calculated 
injection volume, actual volume (in mL) injected and total mg administered will be listed.
7.2
Primary Outcomes
All safety outcomes will be analyzed based on safety population.
7.2.1
Adverse Events
All AEs will be listed (which at least includes subject ID, cumulative dose to date, investigator 
term, Medical Dictionary for Regulatory Activities (MedDRA) coded term, date/study day (from 
initial treatment) for onset and cessation, severity (using the NCIC severity grading), relationship 
to study medication and relationship to IV chemo/other therapy. Deaths (including the cause of 
death if known), AESIs, DLTs and SAEs will be listed separately.
Only treatment emergent adverse events (TEAEs) will be summarized. Two sets of AE 
summaries will be provided: one for AEs up to 12 Weeks and the other for AEs after 12 weeks 
and up to 24 weeks. Summaries of AEs will include:
Overall AE summary, including the number of AEs, serious AEs (SAEs), AEs leading to 
death, and AEs leading to early discontinuation of study;
AEs by System Organ Class (SOC) and Preferred Term (PT);
AEs by SOC, PT, and relationship to NanoPac treatment;
AEs by SOC, PT, and severity;
AEs by SOC, PT and by the number of injections received prior to AE;
SAEs by SOC and PT;
SAEs with relationship to NanoPac by SOC and PT;
AEs leading to death by SOC and PT;
AEs leading to early discontinuation of study by SOC and PT;
AEs of special interest by SOC and PT.
Local AEs by SOC and PT.
All of these summaries will include the counts and frequencies of events, and of subjects who 
had events. 
7.2.2
Laboratory Assessments
Panels and tests in each panel are as follows:
Chemistry : sodium, potassium, chloride, carbon dioxide (CO2), calcium, phosphorus, 
glucose, blood urea nitrogen (BUN), creatinine, alkaline phosphatase, total bilirubin, 
direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), total protein, 
albumin, and calculated creatinine clearance (calculated by stats);


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Hematology : Red blood cell count (RBC), hemoglobin (Hgb), hematocrit (Hct), white 
blood cell count (WBC) including differential, reticulocyte count, platelet count, and 
absolute neutrophil count (ANC);
Urinalysis : specific gravity, hydrogen ion concentration (pH), RBC, WBC, protein, and 
glucose; and urine pregnancy test;
Coagulation : Prothrombin time (PT), activated partial thromboplastin time (PTT), and 
international normalized ratio (INR);
Serology : HIV, Hepatitis B and Hepatitis C.
Laboratory assessments of the panels and tests in each panel including raw assessments at 
each visit and change from baseline for post-baseline visits, will be summarized by visit and 
analyte. Normal/abnormal status and clinical significance (if abnormal) based on investigator 
determination will be summarized qualitatively in the same table.
The result for each non-missing lab analyte will be assigned to a low/normal/high classification 
based on the normal range if available. Shift tables will be provided for change from baseline 
low/normal/high classification to the value at each assessed visit. 
All lab data (including urine pregnancy test at screening, Week 12 and Week 24.) will be listed. 
Clinically significant abnormal lab results will be listed separately. 
7.2.3
Physical Examination
At each visit, the physical examination performance (yes/no), examination date, and change 
from previous visit status will be listed.
7.2.4
Vital Signs and Body Measurements
Vital Signs (systolic and diastolic blood pressure, heart rate, temperature, BMI) and weight will
be summarized for each visit. Change from baseline values for all tests will be summarized at all 
post-baseline visits. BMI at each visit will be calculated based on weight at the visit and height 
at screening.
Vital signs measurements at all visits, including unscheduled visits, will be listed.
7.3
Secondary Outcomes
All efficacy outcomes will be analyzed based on efficacy population.
7.3.1
Paclitaxel Concentration and Presence
For paclitaxel concentration in systemic circulation data, at each scheduled timepoint, the data 
will be summarized; All concentration values with actual sample collection time will be listed;
Mean and individual paclitaxel concentrations over time (in original scale and in logarithm 
transformation) will be graphed by all subjects and by sub-groups.
Presence or absence (absence defined as undetectable = less than lower limit of quantification)
of paclitaxel in lung lesion tissues biopsies prior to each injection of NanoPac will be 


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summarized by injection. All data of presence or absence (and the data of actual measurement)
of paclitaxel with actual sample collection time will be listed. Mean and individual paclitaxel 
concentrations over time (in original scale and in logarithm transformation) will be graphed for all 
subjects and by sub-groups.
7.3.2
Overall and Progression-Free Survival
Survival rates of OS and PFS will be summarized at Week 24 (end of primary study), Week 38 
and Week 52 (end of follow-up) separately based on Kaplan-Meier estimation. Survival times of 
OS and PFS will be listed. Kaplan-Meier plots of OS and PFS will be created for all subjects and 
by sub-groups.
7.3.3
Tumor Measurement and Response
Tumor measurement and response will be summarized for the screening visit and Weeks 12, 
24, 38, and 52:
overall tumor response based on RECIST by tumor volume and longest diameter,
tumor measurements and changes (actual and percentages) from baseline by tumor 
volume and longest diameter,
total number of tumors, total number of nodes, total of all volumes of NanoPac 
calculated and total volume of NanoPac administered.
All variables in CT scan CRF, and the changes from baseline will be listed.
7.4
Exploratory Outcomes
All exploratory outcomes will be analyzed based on safety population.
7.4.1
Eastern Cooperative Oncology Group (ECOG) Scores
ECOG scales will be summarized at each scheduled assessment, and shift tables from baseline 
to each scheduled assessment will be created. All ECOG scale data will be listed.
7.4.2
Pain
VAS pain score and change from baseline will be summarized at all scheduled assessments. 
VAS pain score data will be listed. 
7.4.3
Quality of Life
EQ-5D scores (Mobility, Self-Care, Usual Activities, Pain / Discomfort, and Anxiety/Depression)
will be summarized in frequency. Total health score and change from baseline will be 
summarized. EQ-5D score data will be listed.


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7.4.4
Flow Cytometry (FCM) and Multiplexed immunofluorescense (mIF).
FCM and mIF data will be provided by the Sponsor from the external labs. For FCM, test results 
(including fold change) will be listed. For mIF, test results for whole tissue, with tumor and 
outside tumor will be listed.
7.5
Others  
All other outcomes will be analyzed based on safety population.
7.5.1
Concomitant Medication
Concomitant medications will be summarized by therapeutic drug class (ATC Level 2 code) and 
generic drug name (ATC Level 4 code) using the World Health Organization (WHO) Drug 
Dictionary (WHODD). 
Concomitant medications will be listed by patient.
7.5.2
Concomitant Procedures
The concomitant procedures will be listed.
7.5.3
Concomitant IV Chemotherapy/Radiotherapy/Targeted Therapy Regimen
The concomitant therapy procedures (including therapy name, dose and frequency, cycles 
planned and completed, start and end date etc.) will be listed.
References
None.