Clinical trial NCT03029585
Conditions: Ovarian Carcinoma
Keywords: ovarian carcinoma ovarian cancer ovarian neoplasms ovarian diseases
Sponsor: NanOlogy, LLC
Start date: 2017-04-19; Completion date: 2019-11-04
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate NanoPac® administered intraperitoneally (IP) immediately post-cytoreductive surgery, followed by standard of care (SOC) intravenous (IV) chemotherapy, in women with ovarian cancer. The study will compare IP NanoPac® (plus IV chemotherapy) with SOC IV chemotherapy alone.

Detailed description:
Research has shown that the administration of chemotherapy directly into the peritoneal cavity (intraperitoneal \[IP\] chemotherapy) may provide a significant survival benefit to women with ovarian cancer when combined with cytoreductive surgery and IV chemotherapy.

This study will include a dose-finding phase and an efficacy phase to evaluate IP NanoPac® administered immediately post-cytoreductive surgery in women with ovarian cancer. In the dose-finding phase, subjects will be enrolled in dose-escalated cohorts of three subjects and receive IP NanoPac® at 100, 200, 300, or 400 mg/m2 plus standard of care (SOC) IV chemotherapy. Subjects will be followed for disease status for 12 months. The two best doses from the dose-finding phase will be determined. In the efficacy phase, subjects will be randomized 1:1:1 to one of the two best doses plus SOC IV chemotherapy or SOC alone.

Arms: arm 1: Intraperitoneal NanoPac® 100 mg/m2 applied immediately post-cytoreductive surgery, followed by standard of care intravenous chemotherapy. arm 2: Intraperitoneal NanoPac® 200 mg/m2 applied immediately post-cytoreductive surgery, followed by standard of care intravenous chemotherapy. arm 3: Intraperitoneal NanoPac® 300 mg/m2 applied immediately post-cytoreductive surgery, followed by standard of care intravenous chemotherapy. arm 4: Intraperitoneal NanoPac® 400 mg/m2 applied immediately post-cytoreductive surgery, followed by standard of care intravenous chemotherapy. arm 5: Standard of care intravenous chemotherapy (with platinum and taxane agents) administered per institutional standards.
Interventions: intervention 1: NanoPac® 100 mg/m2 intervention 2: NanoPac® 200 mg/m2 intervention 3: NanoPac® 300 mg/m2 intervention 4: NanoPac® 400 mg/m2 intervention 5: Standard of Care Intravenous Chemotherapy
Intervention descriptions: intervention 1: Single intraperitoneal injection of 100 mg/m2 NanoPac® during cytoreductive surgery, followed by standard-of-care IV carboplatin and IV paclitaxel treatment intervention 2: Single intraperitoneal injection of 200 mg/m2 NanoPac® during cytoreductive surgery, followed by standard-of-care IV carboplatin and IV paclitaxel treatment intervention 3: Single intraperitoneal injection of 300 mg/m2 NanoPac® during cytoreductive surgery, followed by standard-of-care IV carboplatin and IV paclitaxel treatment intervention 4: Single intraperitoneal injection of 400 mg/m2 NanoPac® during cytoreductive surgery, followed by standard-of-care IV carboplatin and IV paclitaxel treatment intervention 5: Cytoreductive surgery followed by standard-of-care IV carboplatin and IV paclitaxel treatment

Protocol documents:
Prot_000.pdf: 
NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19Apr2019 
CONFIDENTIAL 
Page 1 of 42 
 
 
 
US Biotest Protocol #NANOPAC-2016-01 
Phase II Study of Four Dose Levels of Intraperitoneal NanoPac® plus IV 
Carboplatin and Paclitaxel in Patients with Epithelial Ovarian Cancer 
Undergoing Cytoreductive Surgery 
 
IND Number: 
073529 
 
Version: 
 
05 
 
 
Date: 
 
19 April 2019 
 
Sponsor:  
 
NanOlogy, LLC 
231 Bonetti Drive, Suite 240 
San Luis Obispo, CA 93401 
805-595-1300 
 
 
Study Manager: 
Peter Mast 
US Biotest, Inc. 
281-630-6731 
E-mail: peter.mast@usbiotest.com 
 
Medical Director: 
Gere diZerega, MD 
US Biotest, Inc. 
805-630-2800 
E-mail: gere.dizerega@usbiotest.com 
 
 
 




NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 3 of 42 
INVESTIGATOR AGREEMENT AND SIGNATURE FORM 
I have read the attached protocol number 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, Version 05 dated 19 April 2019, 
and agree to comply with the contents of this document. 
I agree to comply with applicable FDA regulations and guidelines set forth in 21 CFR Parts 11, 
50, 54, 56, and 312. 
This document is a confidential communication from 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 
 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 4 of 42 
1 
PROTOCOL SYNOPSIS  
 
Title 
Phase II Study of Four Dose Levels of Intraperitoneal NanoPac® plus IV 
Carboplatin and Paclitaxel in Patients with Epithelial Ovarian Cancer 
undergoing Cytoreductive Surgery 
Sponsor 
NanOlogy, LLC 
Study Number 
NANOPAC-2016-01 
Phase 
II 
Primary Objective • Dose Finding Phase:  Determine the two best dose levels for further 
study  
• Efficacy Phase:  Estimate progression-free survival (PFS) at 12 months 
Secondary 
Objectives 
• Determine the safety of IP NanoPac immediately following 
cytoreductive surgery  
• Perform routine monitoring of plasma paclitaxel concentrations 
following IP administration of NanoPac  
• Compare duration of PFS between time-to-initial recurrence and time-
to-recurrence following second cytoreductive surgery plus IP NanoPac 
• Determine possible predictive factors to be used as stratification factors 
or covariates in subsequent studies  
Safety Monitoring 
Committee 
Prior to the enrollment of the first subject, a Safety Monitoring Committee 
(SMC) Charter will be authored and signed off by the committee 
members; the Charter will contain the data requirements and the decision 
rules for monitoring subject safety during the initial post-surgery outcome 
assessment stage for the escalated doses as well as throughout the trial.  
Study Design 
Phase II study comparing four dose levels of IP NanoPac (100, 200, 300, 
and 400 mg/m2) instilled immediately post-cytoreductive surgery, 
followed by IV chemotherapy (SOC), with SOC only. IV dosing should be 
as per institutional standards. 
The study will include a dose finding phase and an efficacy phase. All 
subjects will have a minimum 12-month follow-up period. Subjects that 
have completed the 12-month follow-up period will be contacted every 6 
months for disease status until disease progression has occurred in 50% of 
the subjects or until 12 months after the last subject completes their IV 
chemotherapy, whichever comes first.  


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 5 of 42 
During the dose finding phase, subjects will be enrolled in dose-escalated 
cohorts of three subjects. All subjects will receive IP NanoPac at 100, 200, 
300, or 400 mg/m2 plus SOC. Subjects will be monitored post-surgery for 
signs of toxicity (e.g., severe abdominal pain after 5-7 days, neutropenia, 
thrombocytopenia, bowel dehiscence, prolonged ileus) and PK plasma 
samples will be taken. The SMC will review all available data up to a 
maximum of four weeks prior to dose escalation. Dose escalation of 
NanoPac will be determined by the SMC per the charter, which will be in 
place prior to the first subject entering the study. This will be repeated for 
each escalated dose until all dose levels have been enrolled or a dose is 
determined to be unsafe. As the IP NanoPac is an adjunctive therapy with 
the same mode of action as the IV chemotherapy, the SMC will be 
reviewing all accumulating information regarding safety. The two best 
dose levels of NanoPac will be included in the efficacy phase of the study. 
In the efficacy phase, subjects will be randomized 1:1:1 to one of two dose 
levels of NanoPac plus SOC or SOC alone.  
Randomization will be determined centrally up to three days prior to 
surgery. Enrollment will be stratified by center, disease stage, whether the 
ovarian cancer is primary or recurrent, and whether they receive 
neoadjuvant chemotherapy.  
The study will continue until disease progression has occurred in 50% of 
the subjects or 12 months after the last subject completes their IV 
chemotherapy, whichever comes first. Disease progression will be 
demonstrated by onset of symptoms, doubling of CA-125, and/or an 
increase in the volume of presumptive tumor burden seen on imaging.  
Population 
Subjects with epithelial ovarian cancer considered appropriate for 
treatment with IV platinum and paclitaxel undergoing cytoreductive 
surgery will be included. 
Study Plan & 
Duration 
Pharmacokinetic (PK) samples will be collected from all  subjects who 
received NanoPac on the day of cytoreductive surgery if clinically 
feasible, at 1, 2, 4, 8, and 24 hours post-instillation, weekly until IV 
chemotherapy begins and at follow-up visits (Months 9 and 12).  
Subjects will be monitored post-surgery through the treatment period for 
safety based on adverse events and laboratory values. Hematology and 
biochemistry will be done weekly until IV chemotherapy begins. 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 6 of 42 
PK, hematology, and biochemistry samples will be collected from every 
subject prior to each cycle of post-surgery IV chemotherapy.  
Imaging will be performed prior to initiation of post-surgery IV 
chemotherapy to establish baseline tumor burden, after cycle 3, and at the 
end-of-treatment (EOT) visit.  
Baseline CA-125 levels will be established prior to post-surgery cycle 2, 
and subsequent CA-125 testing will be performed at each cycle and 
following the last cycle.  
If the CA-125 level is double the baseline level for 2 consecutive cycles, 
or if progression is suspected, imaging will be conducted.  
During the minimum 12-month follow-up period, subjects will return to 
the clinic every 3 months for CA-125, PK sample collection, as well as 
clinical evaluation of the subject for signs or symptoms of disease 
progression. Imaging will be performed when a subject develops 
symptoms, has a doubling of CA-125, or every 6 months, whichever is 
sooner. After 12 months of follow-up, subjects will be contacted every 6 
months until disease progression has occurred in 50% of the subjects or 12 
months after the last subject completes their IV chemotherapy, whichever 
comes first.  
The duration of the study will be approximately 6 months of treatment 
with a minimum of 12 months’ follow-up per subject. 
Medication/Dosage 
NanoPac 100, 200, 300, and 400 mg/m2 administered IP immediately post 
cytoreductive surgery followed by IV chemotherapy (SOC), or SOC 
alone.  
Sample Size 
Dose finding phase:  Approximately 16 subjects 
Efficacy phase:  Approximately 45 subjects 
Safety Variables 
• Adverse events 
• Laboratory assessments 
• ECOG performance status 
Efficacy Variables 
• CA-125 level 
• Tumor burden (residual disease) shown by imaging and calculated per 
RECIST (version 1.1) criteria 
• Progression-free survival (PFS) 
• Survival 
• Cancer-related symptoms (including bowel obstruction, ascites) 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 7 of 42 
Inclusion Criteria 
• Epithelial ovarian cancer which is contained within the abdomen, but 
may include pleural effusion if that is the limit of non-peritoneal cavity 
disease. If subject has recurrent epithelial ovarian cancer, the disease 
must be platinum-sensitive (recurrence >6 months from prior 
chemotherapy regimen that included a platinum agent and cytoreductive 
surgery)   
• Subject appropriate for cytoreductive surgery and treatment with IV 
platinum and paclitaxel  
• Minimal or non-symptomatic ascites 
• ≥18 years old 
• Signed informed consent 
Exclusion Criteria 
• Epithelial ovarian cancer outside of the peritoneal cavity, with the 
exception of pleural effusions 
• Anticipated use of concomitant chemotherapy (other than the protocol-
specified agents), immunotherapy, or radiation therapy 
• Treatment with a prior investigational agent within 30 days of planned 
instillation of NanoPac, with the exception of subjects participating in 
poly (ADP-ribose) polymerase (PARP) inhibitor trials.  These subjects 
must discontinue the investigational agent prior to surgery 
• Known sensitivity to any of the study medication components or the 
chemotherapy regimen 
• History of prior malignancy other than ovarian that has not been in 
remission for >5 years, with the exception of basal cell or squamous cell 
carcinoma or cervical carcinoma in situ on biopsy 
• Ileostomy or hepatic resection during current cytoreductive surgery 
• Women of childbearing potential not practicing adequate forms of birth 
control 
Statistical Methods Prior to the enrollment of the first subject, a Safety Monitoring Committee 
(SMC) Charter will be authored and signed off by the committee 
members; the Charter will contain the data requirements and the decision 
rules for monitoring subject safety during the initial post-surgery outcome 
assessment stage for the escalated doses as well as throughout the trial.  
The data will be summarized in two periods – the dose finding phase, 
where the highest doses which are considered safe will be assessed, and 
the comparative phase. The comparative phase is the primary period for 
defining the success of the addition of IP NanoPac to the SOC. 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 8 of 42 
The data from the dose finding phase will be summarized descriptively by 
dose level. The PK data will be reviewed and the data presented to 
determine a possible relationship to safety, e.g., frequency of pre-specified 
AEs. Any efficacy data available (e.g., CA-125 and/or RECIST criteria as 
well as PFS and survival, if available) will be presented in a similar 
manner.  
The comparative part of the trial, with approximately 15 subjects per 
treatment arm, has not been powered for inferential statistics; however, 
comparisons to SOC-only may be performed to provide guidance for the 
clinical interpretation of an effect which is clinically better than the 
control. It is recognized that all these inferential results should be viewed 
and interpreted with caution. The criteria defining the NanoPac dose to 
move forward for further study will be based on both safety and 
indications of efficacy. 
In addition, the subjects will enter a post-treatment follow-up phase and be 
monitored for a minimum of 12 months post-chemotherapy to determine 
short-term PFS and survival status. The data will at a minimum be 
displayed as a Kaplan-Meier plot; appropriate descriptive summary 
statistics will also be presented. 
Patients will be monitored throughout chemotherapy to assess the adverse 
experiences associated with the mode of administration and the toxicity of 
the chemotherapy. The events from the monotherapy stage (surgery to 
initiation of IV chemotherapy) and the adjunctive therapy stage (from 
initiation of post-surgery IV chemotherapy until the end of the trial) will 
be presented separately; the start date will be the indicator of the stage that 
the event is associated with. Special focus will be on those events which 
lead to termination of IV chemotherapy. 
 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 9 of 42 
2 
TABLE OF CONTENTS 
1 
PROTOCOL SYNOPSIS ...................................................................................................... 4 
2 
TABLE OF CONTENTS ...................................................................................................... 9 
3 
LIST OF ABBREVIATIONS ............................................................................................. 11 
4 
INTRODUCTION ............................................................................................................... 12 
4.1 
Background ............................................................................................................... 12 
4.2 
Investigational Agent NanoPac ................................................................................ 12 
4.2.1 Clinical Trials with NanoPac .......................................................................... 13 
4.3 
Rationale for the Study ............................................................................................. 13 
4.4 
Dose Justification ...................................................................................................... 14 
5 
STUDY OBJECTIVES ....................................................................................................... 14 
6 
INVESTIGATIONAL PLAN ............................................................................................. 14 
6.1 
Overall Study Plan .................................................................................................... 14 
6.1.1 Study Design .................................................................................................... 14 
6.2 
Sample Size .............................................................................................................. 16 
6.3 
Investigational Sites .................................................................................................. 16 
6.4 
Study Duration .......................................................................................................... 17 
7 
SELECTION AND ENROLLMENT OF STUDY POPULATION ................................ 17 
7.1 
Eligibility Considerations ......................................................................................... 17 
7.1.1 Inclusion Criteria ............................................................................................. 17 
7.1.2 Exclusion Criteria ............................................................................................ 17 
7.2 
Enrollment and Randomization ................................................................................ 18 
7.3 
Removal of Patients from Assessment ..................................................................... 18 
8 
STUDY PROCEDURES AND TREATMENTS ............................................................... 19 
8.1 
Study Procedures ...................................................................................................... 19 
8.1.1 Screening and Baseline .................................................................................... 19 
8.1.2 Treatment Cycles ............................................................................................. 20 
8.1.3 12-Month Follow-Up Period ........................................................................... 22 
8.1.4 Clinical Laboratory Testing ............................................................................ 22 
8.2 
Schedule of Study Procedures and Events ................................................................ 23 
8.3 
Treatments ................................................................................................................ 24 
8.3.1 Investigational Agent ....................................................................................... 24 
8.3.2 IV Chemotherapy ............................................................................................. 25 
8.3.3 Concomitant Medications and Treatments ...................................................... 25 
8.3.4 Prohibited, Excluded, and Contraindicated Medications and Treatments ..... 26 
9 
ADVERSE EVENT REPORTING .................................................................................... 26 
9.1 
Adverse Event ........................................................................................................... 26 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 10 of 42 
9.1.1 Relationship to Investigational Agent .............................................................. 27 
9.1.2 Severity ............................................................................................................ 27 
9.2 
Serious Adverse Event (SAE) .................................................................................. 28 
9.3 
Pregnancy ................................................................................................................. 29 
10 EFFICACY AND SAFETY VARIABLES ........................................................................ 29 
10.1 
Efficacy Variables .................................................................................................... 29 
10.2 
Safety Variables ........................................................................................................ 30 
11 STATISTICAL CONSIDERATIONS ............................................................................... 30 
11.1 
Sample Size Estimations ........................................................................................... 31 
11.2 
Populations ............................................................................................................... 31 
11.3 
Missing Data ............................................................................................................. 31 
11.4 
Subject Disposition and Characteristics ................................................................... 31 
11.5 
Primary Safety Outcome ........................................................................................... 32 
11.6 
Primary Efficacy Outcome ....................................................................................... 32 
11.7 
Treatment-Related Information ................................................................................ 33 
11.8 
Pharmacokinetics ...................................................................................................... 33 
11.9 
Safety Outcomes ....................................................................................................... 34 
11.10 Concomitant Medication .......................................................................................... 34 
11.11 Safety Monitoring Committee (SMC) ...................................................................... 34 
11.12 Interim Analysis ........................................................................................................ 34 
12 DATA QUALITY ASSURANCE ....................................................................................... 34 
12.1 
Monitoring ................................................................................................................ 35 
12.2 
Source Documents .................................................................................................... 35 
12.3 
Electronic Case Report Forms (eCRFs) ................................................................... 36 
12.4 
Disposition of Clinical Supplies ............................................................................... 36 
13 ETHICS ................................................................................................................................ 36 
13.1 
Institutional Review Board/Ethics Committee ......................................................... 36 
13.2 
Ethical Conduct of the Study .................................................................................... 37 
13.3 
Patient Information and Consent .............................................................................. 37 
13.4 
Protocol Amendments .............................................................................................. 37 
13.5 
Confidentiality .......................................................................................................... 38 
14 STUDY ADMINISTRATIVE STRUCTURE ................................................................... 38 
14.1 
Sponsor Contacts ...................................................................................................... 38 
14.2 
Maintenance of Study Records ................................................................................. 38 
14.3 
Final Report .............................................................................................................. 39 
14.4 
Publication and Use of Study Findings .................................................................... 39 
14.5 
Liability and Insurance ............................................................................................. 39 
15 REFERENCES .................................................................................................................... 41 
APPENDIX A:  ECOG PERFORMANCE STATUS SCALE ................................................ 42 
 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 11 of 42 
3 
LIST OF ABBREVIATIONS 
AUC 
Area under the Curve 
AE 
Adverse Event 
Cmax 
Maximum (Peak) Plasma Concentration of a Drug 
DLT 
Dose Limiting Toxicity 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EOT 
End-of-Treatment 
FDA 
The U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
IND 
Investigational New Drug Application 
IP 
Intraperitoneal  
IV 
Intravenous 
MTD 
Maximum Tolerated Dose 
NDA 
New Drug Application 
PCA 
Precipitation with Compressed Antisolvents 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
RECIST Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SMC 
Safety Monitoring Committee 
SOC 
Standard of Care 
TEAE 
Treatment-Emergent Adverse Event 
Tmax 
Time at which Maximum (Peak) Plasma Concentration of a Drug (Cmax) is 
observed 
TTP 
Time to Progression 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 12 of 42 
4 
INTRODUCTION 
4.1 
Background 
Ovarian cancer has a high rate of recurrence, even when treated with the current standard of care. 
When ovarian cancer recurs, treatment is challenging and disease-free intervals are brief. The 
addition of intraperitoneal (IP) therapy is an attractive option for primary or recurrent ovarian 
cancer. The basic goal of intraperitoneal antineoplastic therapy is to expose cancer confined to 
the peritoneal cavity to higher concentrations of drug for longer periods of time than is possible 
with systemic therapy. Intraperitoneal therapy is designed to maximize drug delivery to the 
tumor while sparing the patients many of the systemic toxicities associated with the drug. A 
number of Phase II trials have documented the feasibility and clinical activity of the 
intraperitoneal approach in epithelial ovarian cancer. 
Paclitaxel has broad antitumor activity and may provide a therapeutic advantage with IP 
administration. Paclitaxel is a naturally occurring diterpenoid isolated from the bark of the 
Pacific yew tree, and has exhibited some success in the treatment of several types of cancers, 
including ovarian, breast, and lung cancer. Paclitaxel drug substance has been available in 
commercial drug products in the United States for over 20 years (Taxol®, NDA 20-262, Bristol-
Myers Squibb, approved for marketing on December 29, 1992; also generic paclitaxel drug 
product). The formulation of Taxol is a 6 mg/mL solution in a 50:50 (v/v) mixture of 
Cremophor® EL (polyethoxylated castor oil) and dehydrated ethanol. However, significant side 
effects, including severe anaphylactic hypersensitivity reactions, hyperlipidemia, abnormal 
lipoprotein patterns, aggregation of erythrocytes, and peripheral neuropathy, have been observed 
with this commercial formulation. These side effects have been attributed to the Cremophor EL 
excipient. Due to paclitaxel’s significant potential as an effective chemotherapeutic, the search 
for alternative formulations that may be safer and better tolerated has been extensive. 
4.2 
Investigational Agent NanoPac 
NanOlogy, LLC, has produced a formulation of nanoparticulate paclitaxel, identified as 
NanoPac® (Sterile Nanoparticulate Paclitaxel) Powder for Suspension (“NanoPac”), which is the 
subject of this protocol. 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, 
306 mg of the paclitaxel nanoparticle powder is filled into a 60 mL Type 1, USP, clear-glass vial, 
closed with a stopper, sealed with an aluminum crimp seal, and sterilized by gamma irradiation. 
Prior to administration at the hospital/clinic, the dry, sterilized NanoPac will be reconstituted 
with 1% polysorbate 80 reconstitution solution and 0.9% Sodium Chloride for Injection, USP, to 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 13 of 42 
form a suspension. The suspension should be kept at room temperature and must be administered 
within 8 hours of reconstitution; the suspension must not be frozen or refrigerated. Detailed 
instructions are included in the dose kit.  
4.2.1 Clinical Trials with NanoPac 
The safety of NanoPac, previously called Nanotax®, was investigated in Protocol HSC#11140, 
“A Phase I Study of Intraperitoneal Nanoparticle Paclitaxel in Patients with Peritoneal 
Malignancies.” To date, this is the only clinical study that has been conducted with NanoPac. 
The results of this study were published in the journal Cancer Chemotherapy and Pharmacology 
(Williamson 2015). 
Protocol HSC#11140 was a dose-escalating study evaluating IP-administered Nanotax at doses 
of 50-275 mg/m2 given every 28 days until disease progression or unacceptable toxicity 
occurred. Twenty-two patients were enrolled in Protocol HSC#11140, 21 patients received 
Nanotax, and a total of 43 doses of Nanotax were administered at doses up to 275 mg/m2. IP 
administration of Nanotax did not lead to increases in systemic toxicity over that typically 
associated with IV paclitaxel. No Grade 2 or higher neutropenia and/or Grade 3 or higher 
neurologic toxicities were reported. Grade 3 thrombocytopenia, considered unlikely to be related 
to study medication, occurred in one patient. The peritoneal concentration-time profile of 
paclitaxel rose during the two days after dosing to peritoneal fluid concentrations 450-2900 times 
greater than peak plasma drug concentrations and remained elevated through the entire dose 
cycle. Best response assessments were made in 16 of the 21 subjects. Four subjects were 
assessed as stable or had no response and twelve patients had progressive disease. Five of 21 
patients with advanced cancers survived longer than 400 days after initiation of IP Nanotax 
treatment. 
Additional data from this clinical trial is presented in the NanoPac Investigator’s Brochure. 
4.3 
Rationale for the Study 
The rationale for administration of NanoPac via the intraperitoneal route is three-fold: 1) greater 
concentrations of paclitaxel will be achieved within the peritoneal cavity compared to IV 
administration of this agent; 2) nanoparticulate paclitaxel will undergo prolonged dissolution 
resulting in greater paclitaxel concentrations at the tumor site for a longer period of time 
compared to IV paclitaxel alone; and 3) substantially less systemic exposure to paclitaxel will 
result from IP NanoPac administration as compared to IV paclitaxel, thus reducing the risk of 
additional systemic toxicity.  


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 14 of 42 
This Phase II study will include patients with epithelial ovarian cancer undergoing cytoreductive 
surgery. The study design allows for a safety evaluation of IP NanoPac immediately following 
surgery as well as preliminary efficacy determination of IP NanoPac in combination with IV 
paclitaxel and carboplatin versus IV paclitaxel and carboplatin alone. The population selected is 
expected to benefit from the IP NanoPac.  
4.4 
Dose Justification 
The most common dose of paclitaxel used via the IP route is 60 mg/m2, with toxicities linked to 
the Cremophor EL as well as systemic toxicities. In the Phase I NanoPac study, doses up to 275 
mg/m2 were found to be safe. The proposed starting dose in the dose finding phase of this study 
is 100 mg/m2, rising to 200, 300 and 400 mg/m2. The dose finding phase is designed to 
determine the best tolerated dose of IP NanoPac in the pre-defined series of doses, and establish 
the safety of instilling NanoPac at the time of surgery as well as the safety of IP instillation 
followed by IV treatment.  
5 
STUDY OBJECTIVES 
The primary objectives of this study are (a) to determine the two best dose levels of IP NanoPac 
given at the time of surgery; and (b) to determine progression-free survival (PFS) at 12 months. 
Secondary objectives are to determine the safety of IP NanoPac immediately following 
cytoreductive surgery, to compare duration of PFS between time-to-initial recurrence and time-
to-recurrence following second cytoreductive surgery plus IP NanoPac in those subjects with 
recurrent cancer, to determine plasma paclitaxel concentrations following IP administration of 
NanoPac, and to determine possible predictive factors to be used as stratification factors or 
covariates in subsequent studies.  
6 
INVESTIGATIONAL PLAN 
6.1 
Overall Study Plan 
This is a Phase II study of four dose levels of IP NanoPac plus IV carboplatin and paclitaxel 
(SOC) in patients with epithelial ovarian cancer undergoing cytoreductive surgery. 
6.1.1 Study Design 
Subjects with epithelial ovarian cancer considered appropriate for treatment with IV platinum 
and paclitaxel undergoing cytoreductive surgery will be included. The study will include a dose 
finding phase and an efficacy phase. 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 15 of 42 
Dose Finding Phase 
Subjects will be enrolled in dose-escalated cohorts and will receive IP NanoPac at a dose level of 
100, 200, 300, or 400 mg/m2 plus SOC. During the dose finding phase the study will follow a 
standard 3+3 dose-ascending design, commencing treatment on Day 1 with 100 mg/m2. If a 
single dose limiting toxicity (DLT) is identified in 1 of 3 subjects in the cohort, a further 3 
subjects will be enrolled at the same dose level. If ≥ 1 more of the same DLT occurs in the 3 
extra subjects enrolled in the cohort, dose escalation will stop and the prior dose level will be 
regarded as the Maximum Tolerated Dose (MTD) and taken forward into the dose expansion 
phase. If no further DLT are identified, dose escalation will continue, until either a DLT is 
identified at a higher dose or the top dose of 400 mg/m2 is reached.  
Subjects will be monitored post-surgery for signs of toxicity (e.g., severe abdominal pain after 5-
7 days, neutropenia, thrombocytopenia, bowel dehiscence, and prolonged ileus) and PK plasma 
samples will be taken. The Safety Monitoring Committee (SMC) will review the accumulating 
data for up to a maximum of four weeks per subject prior to dose escalation and approve moving 
to the next dose cohort or adding subjects to the current dose level if an IP NanoPac-related 
adverse effect is determined to be dose-limiting. This will be repeated for each escalated dose 
until all dose levels have been enrolled or a dose is determined to be unsafe. As the NanoPac is 
an adjunctive therapy with the same mode of action as the IV chemotherapy, the SMC will be 
reviewing all accumulating information regarding safety. The two best dose levels of NanoPac 
will be included in the efficacy phase of the study. 
Examples of what might be regarded as a DLT are listed below: 
Non Hematologic: 
• Grade 3 or higher non-hematological toxicity, excluding nausea, vomiting, 
diarrhea; 
• Grade 3 or higher nausea, vomiting, or diarrhea uncontrolled by maximal 
antiemetic/ antidiarrheal therapy for greater than 24 hours; 
• Any toxicity which in the judgment of the Medical Monitor, Principal 
Investigator, Sponsor Medical Director, or SMC is considered a DLT; 
• Hypersensitivity reactions to NanoPac that cannot be controlled with standard 
treatment. 
Hematologic: 
• Grade 3 or higher anemia and/or neutropenia; 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 16 of 42 
• Thrombocytopenia of any Grade if associated with clinically significant bleeding 
(clinically significant as determined by the investigator, or results in a transfusion 
of red blood cells.), or Grade 4 thrombocytopenia without bleeding. 
 
Efficacy Phase 
Subjects will be randomized 1:1:1 to one of two dose levels of NanoPac plus SOC, or SOC 
alone. The study will continue until disease progression has occurred in 50% of the subjects or 
12 months after the last subject completes post-surgery IV chemotherapy, whichever comes first. 
Disease progression will be demonstrated by onset of symptoms, doubling of CA-125, and/or a 
20% increase in the volume of presumptive tumor burden seen via imaging.  
Pharmacokinetic (PK) samples will be collected from all subjects who received NanoPac on Day 
1, at 1, 2, 4, 8, and 24 hours post-instillation, if clinically feasible, weekly until post-surgery IV 
chemotherapy begins, prior to each post-surgery cycle of IV chemotherapy and at the Month 9 
and Month 12 follow-up visits. Imaging will be done prior to initiation of post-surgery IV 
chemotherapy to establish baseline tumor burden. A baseline CA-125 level will be established 
prior to cycle 2, post-surgery, and subsequent testing will be performed at each cycle and 
following the last cycle. If the CA-125 level is double the baseline level for 2 consecutive cycles, 
or if progression is suspected imaging will be conducted.  
All subjects will have a minimum 12-month follow-up period, during which subjects will return 
to the clinic every 3 months for CA-125 determination, PK sample collection, as well as clinical 
evaluation for signs or symptoms of disease progression. Imaging will be performed when a 
subject develops symptoms, has a doubling of CA-125, or every 6 months, whichever is sooner. 
After 12 months of follow-up, subjects will be contacted every 6 months until disease 
progression has occurred in 50% of the subjects or 12 months after the last subject completes 
their IV chemotherapy, whichever comes first.  
6.2 
Sample Size 
During the dose finding phase, approximately 16 subjects will be enrolled. During the efficacy 
phase, approximately 45 subjects will be randomized.  
6.3 
Investigational Sites 
Up to 12 investigational sites in the United States will be used for this study. Sites will be 
selected based on the experience of the Investigator in the treatment of epithelial ovarian cancer, 
the number of appropriate potential study subjects available from the center’s patient population 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 17 of 42 
and the experience of the site’s Investigator and study staff with the treatment of clinical research 
subjects.  
6.4 
Study Duration 
The overall study duration is estimated to be 30 months: 12 months’ enrollment, approximately 6 
months of treatment, and a minimum of 12 months of follow-up for each subject.   
7 
SELECTION AND ENROLLMENT OF STUDY POPULATION 
7.1 
Eligibility Considerations 
7.1.1 Inclusion Criteria 
Patients who meet the following criteria will be considered eligible for participation in 
the study: 
1) 
Signed informed consent 
2) 
Epithelial ovarian cancer which is contained within the abdomen, but may include 
pleural effusion if that is the limit of non-peritoneal cavity disease. If subject has 
recurrent epithelial ovarian cancer, the disease must be platinum-sensitive 
(recurrence >6 months from prior chemotherapy regimen that included a platinum 
agent and cytoreductive surgery)   
3) 
Subject appropriate for cytoreductive surgery and treatment with IV platinum and 
paclitaxel  
4) 
Minimal or non-symptomatic ascites 
5) 
≥18 years old 
7.1.2 Exclusion Criteria 
If a subject meets any of the following criteria, she must be excluded from the study: 
1) 
Epithelial ovarian cancer outside of the peritoneal cavity, with the exception of 
pleural effusions 
2) 
Anticipated use of concomitant chemotherapy (other than the protocol specified 
agents), immunotherapy, or radiation therapy 
3) 
Treatment with a prior investigational agent within 30 days of planned instillation 
of NanoPac, with the exception of subjects participating in poly (ADP-ribose) 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 18 of 42 
polymerase (PARP) inhibitor trials.  These subjects must discontinue the 
investigational agent prior to surgery 
4) 
Known sensitivity to any of the study medication components or the chemotherapy 
regimen 
5) 
History of prior malignancy other than ovarian that has not been in remission for >5 
years, with the exception of basal cell or squamous cell carcinoma or cervical 
carcinoma in situ on biopsy 
6) 
Ileostomy or hepatic resection during current cytoreductive surgery  
7) 
Women of childbearing potential not practicing adequate forms of birth control 
7.2 
Enrollment and Randomization 
After written informed consent is obtained, the subject will be assigned a subject number and 
will be considered enrolled in the study. Subject numbers will be assigned sequentially by the 
site and used to identify the subject on all study documents, including the Case Report Form 
(eCRF). If a subject does not qualify for the study or is withdrawn from the study, the subject 
number will not be reassigned. 
In the dose finding phase, subjects will be assigned to IP plus IV chemotherapy. In the efficacy 
phase subjects will be randomized 1:1:1 to the two best NanoPac dose levels plus IV 
chemotherapy, or to IV chemotherapy alone. Randomization will be determined centrally. 
Enrollment will be stratified by center, disease stage, whether the ovarian cancer is primary or 
recurrent, and whether they receive neoadjuvant chemotherapy. Subjects will be monitored post-
surgery for signs of toxicity (e.g., severe abdominal pain after 5-7 days, neutropenia, 
thrombocytopenia, bowel dehiscence, prolonged ileus), and hematology, biochemistry, and PK 
plasma samples will be taken. The SMC will review the accumulating data for up to a maximum 
of four weeks prior to dose escalation per subject. Dose escalation of NanoPac will be 
determined by the SMC per the charter, which will be in place prior to the first subject entering 
the study.  
7.3 
Removal of Patients from Assessment 
All subjects removed from the study due to adverse events will remain under investigation until 
conditions requiring removal are resolved or stabilized and will continue to be followed for at 
least 6 months after instillation of NanoPac to assess adverse events and disease status.  
Subjects may be discontinued from the study for any of the following reasons: 
1. Lack of cooperation with the requirements of the study; 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 19 of 42 
2. Intercurrent illness that, in the opinion of the Investigator, will affect the patient’s ability 
to conform to the study protocol; 
3. Withdrawal of consent; or 
4. At the direction of the Medical Monitor. 
The Sponsor should be notified immediately when a subject is removed or withdrawn from the 
study after treatment with Investigational Agent has commenced.  
Subjects who refuse or fail to appear for clinic visits and fail to respond to or cooperate with 
reasonable and diligent attempts at contact should be considered lost-to-follow-up. Attempts at 
contact should be recorded in subject records.  
8 
STUDY PROCEDURES AND TREATMENTS 
8.1 
Study Procedures 
8.1.1 Screening and Baseline 
Prior to enrollment in the study, the following procedures and assessments must be completed, 
documented and reviewed by the Investigator within 14 days prior to cytoreductive surgery: 
• Written informed consent including comprehensive discussion of the study schedule, 
procedures and subject protocol requirements; 
• Complete medical history, including review of previous medical records, demographics and 
parity; 
• Review and documentation of epithelial ovarian cancer diagnosis, highest recorded CA-125 
level, and previous treatments including surgical, radiotherapy, and chemotherapeutic 
records. A copy of the pathology report confirming the de novo diagnosis of epithelial 
ovarian cancer or the diagnosis of recurrent platinum-sensitive epithelial ovarian cancer must 
be filed in the subject’s study record;  
• Review and documentation of all concomitant prescription and non-prescription medications, 
at the time of screening; 
• Comprehensive physical examination, including ECOG Performance Status assessment (see 
Appendix A), gynecological exam and vital signs (blood pressure, heart rate, respiration rate, 
temperature, body weight and height); 
• Sample collection and processing for clinical laboratory assessments as follows:  
o 
Blood urea nitrogen (BUN), creatinine, total bilirubin, direct bilirubin (if total is 
abnormal), aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
albumin; 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 20 of 42 
o 
Red blood cell count (RBC), hemoglobin (Hgb), hematocrit (Hct), white blood cell 
count (WBC) including differential, reticulocyte count, and platelet count; 
o 
Urinalysis including hydrogen ion concentration (pH), RBC, WBC, protein, and 
glucose; 
o 
Serum pregnancy test, if the subject is not surgically sterile or post-menopausal; 
• Review of inclusion and exclusion criteria and determination of eligibility.  
8.1.2 Treatment Cycles 
Subjects receiving NanoPac will have IP instillation of the NanoPac at the time of cytoreductive 
surgery (see Section 8.3.1). Full debulking is not required (if not feasible), however Investigator 
assessment of residual disease is required following surgery.  All subjects are expected to initiate 
IV carboplatin and IV paclitaxel treatment following cytoreductive surgery. IV carboplatin and 
IV paclitaxel will be administered, either every 21 days or on a dose dense schedule for six 
cycles (SOC).  Bevacizumab may be added to the SOC regimen at the Investigator’s discretion, 
as long as it is initiated at least 6 weeks post-surgery. 
The SOC is expected to remain the same for all cycles of treatment. However, the regimen can 
be modified after cycle 1 if, in the investigator’s opinion, that change is best for the subject and 
the new treatment does not involve an investigational agent. Dosing and dose adjustments should 
be as per institutional standards. 
Plasma samples for PK analysis will be taken on Day 1 at 1, 2, 4, 8, and 24 hours post-
intraperitoneal (IP) instillation of NanoPac, if clinically feasible, and weekly thereafter until IV 
chemotherapy begins, to provide information on resulting paclitaxel systemic exposure in 
subjects who receive IP NanoPac. Additionally, a PK sample will be collected prior to each post-
surgery cycle of IV chemotherapy and at the month 9 and month 12 follow-up visits. 
Hematology and biochemistry assessments will be done weekly between surgery and initiation of 
IV chemotherapy. Imaging will be done prior to initiation of post-surgery IV chemotherapy to 
establish baseline tumor burden.  
Patients who, in the PI’s judgement, will benefit from IV carboplatin and paclitaxel 
chemotherapy in advance of their cytoreductive surgery and who meet all other enrollment 
criteria may be enrolled in the study.  For these subjects, the pre-surgery chemotherapy will be 
recorded in the prior cancer treatment section of the eCRF and the post-surgery chemotherapy 
will be recorded in the IV chemotherapy section of the eCRF, with the first post-surgery cycle 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 21 of 42 
designated as cycle 1.  Imaging will be done prior to post-surgery IV chemotherapy to establish 
baseline tumor burden.     
Post-surgery IV Chemotherapy 
On Day 1 of each post-surgery IV chemotherapy treatment cycle the following procedures will 
be performed: 
• Review of any changes in physical condition or symptoms 
• Review of concomitant medications and therapies 
• Brief physical exam including vital signs (blood pressure, heart rate, respiration rate and 
body weight) 
• Blood sampling (hematology, biochemistry, and PK)  
• Calculation of body surface area for determination of chemotherapy dose and administration 
of the following chemotherapy regimen:  
o Intravenous carboplatin at a dose of AUC 5 to 6 
o Intravenous paclitaxel at a dose of 175 mg/m2 given every 21 days, or 80 mg/m2 given 
weekly 
o Note that in the case of allergic reaction cisplatin can be used instead of carboplatin. 
Dosing should be as per institutional standards. 
• Review and documentation of adverse events and changes in symptoms. 
 
Imaging will be done following cycle 3 and cycle 6. If 4 cycles, or less, of IV chemotherapy will 
be given post-surgery, imaging will be conducted following the last cycle. If more than 4 cycles 
of IV chemotherapy will be given post-surgery, imaging will be conducted following cycle 3 and 
the last cycle. Tumor burden and response will be determined using RECIST (version 1.1) 
criteria. 
Prior to IV chemotherapy cycle 2, a baseline CA-125 level will be established. Subsequent 
testing will be performed at each cycle and following the last cycle. If CA-125 level is double the 
baseline level for two consecutive cycles, or if progression is suspected, imaging will be 
conducted.  
The End-of-Treatment (EOT) visit will take place after the last cycle of IV chemotherapy. This 
visit will include: 
• Review of any changes in physical condition or symptoms 
• Review of concomitant medications and therapies 
• Brief physical exam including vital signs (blood pressure, heart rate, respiration rate and 
body weight) 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 22 of 42 
• Blood sampling (hematology, blood chemistry, CA-125) 
• 
Urinalysis 
• 
Imaging  
8.1.3 12-Month Follow-Up Period 
Following completion of the post-surgery IV chemotherapy, a minimum 12-month follow-up 
period will occur. The follow-up period will begin at the EOT visit (at the end of the final cycle 
of chemotherapy). Subjects will return to the clinic every 3 months for CA-125 determination, 
PK sample collection, as well as clinical evaluation of signs or symptoms of disease progression. 
Imaging will be performed when a subject develops symptoms, has a doubling of CA-125, or 
every 6 months, whichever is sooner.  
Subjects that have completed the 12-month follow-up period will be contacted every 6 months 
for disease status until disease progression has occurred in 50% of the subjects or until 12 
months after the last subject completes their IV chemotherapy, whichever comes first.  
8.1.4 Clinical Laboratory Testing 
Clinical laboratory tests required by the protocol will be performed by the local lab. Laboratory 
testing will be conducted at baseline, at the beginning of every post-surgery IV chemotherapy 
cycle, and at the EOT visit. 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19Apr2019 
CONFIDENTIAL 
Page 23 of 42 
8.2 
Schedule of Study Procedures and Events 
 
Screening  
Surgery 
Surgery
-to-IV 
IV Chemotherapy (Q21dx6)10 
End-of-
Treatment6 
Follow-Up 
Cycle 
1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Q3monx4 
Q6mon 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
History1 
X 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
X 
 
 
ECOG 
X 
 
 
 
 
 
 
 
 
X 
 
 
Hematology2,4 
X 
 
X2 
X4 
X4 
X4 
X4 
X4 
X4 
X 
 
 
Biochemistry2,4 
X 
 
X2 
X4 
X4 
X4 
X4 
X4 
X4 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
X 
 
 
CA-125 
X8 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
PK Samples2 
 
X9 
X2 
X 
X 
X 
X 
X 
X 
 
X 
 
Surgery, Staging, Residual 
disease, Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
NanoPac7 Instillation 
 
X 
 
 
 
 
 
 
 
 
 
 
Radiologic Assessment 3 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
IV Chemotherapy10 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Events5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Disease status 
 
 
 
 
 
 
 
 
 
 
 
X 
1 
History includes all events before initiation of NanoPac treatment  
2 
PK (in NanoPac subjects only), hematology, and biochemistry to be done weekly in the period between surgery and the start of IV chemotherapy  
3 
Radiologic assessment is an abdominal/pelvic CT or MRI and the initial study images should be post-debulking surgery, but prior to the initiation of post-surgery IV chemotherapy. Once IV 
chemotherapy has started, imaging is to be conducted following cycle 3, at EOT, and when CA-125 is doubled from baseline for two consecutive assessment points or when progression is 
suspected or every 6 months during the 12-month follow-up period. If ≤4 cycles of IV chemotherapy will be given post-surgery, imaging will be conducted following the last cycle.  If >4 cycles of 
IV chemotherapy will be given post-surgery, imaging will be conducted following cycle 3 and the last cycle.  
4 
Bloodwork should be done within 24 hours prior to Day 1 of any cycle, but up to 72 hours prior is acceptable 
5 
Adverse event collection will start immediately following initiation of study treatment and conclude one month following last administration of post-surgery IV chemotherapy 
6 
End-of-treatment assessments will be done at the point the subject discontinues post-surgery IV chemotherapy (e.g., day 21 (+/- 7 days) of cycle 6 or last cycle administered) 
7 
NanoPac applies only to those randomized to NanoPac 
8 
Screening CA-125 is the highest recorded CA-125 level for the subject up until screening for this study 
9 
PK samples on day of surgery, after NanoPac instillation are 1 and 2 hours (+/- 15 min.), 4 and 8 hours (+/- 30 min.), and 24 hours (+/- 2 hours) 
10 
The schedule for neoadjuvant and post-surgery chemotherapy will be at the Investigator’s discretion and may be different than the planned six cycles post-surgery. 
 


NanOlogy, LLC 
Clinical Study Protocol 
 
NANOPAC-2016-01 
Version:  04 
26Jul2017 
CONFIDENTIAL 
Page 24 of 42 
8.3 
Treatments 
8.3.1 Investigational Agent 
Investigational Agent for all treatment groups will be supplied to the site in kits with a 60 cm3 
vial containing 306 mg of NanoPac powder and a smaller vial with 7 mL of reconstitution 
solution (1% Polysorbate 80 in 0.9% Sodium Chloride for Injection, USP). The site will be 
responsible for providing 0.9% Sodium Chloride for Injection, USP.  
Dosing solution will be prepared as follows:  
NanoPac suspension procedure: 
• Using a syringe with a 27-gauge needle or larger, add 5.0 mL of the sterile 1% polysorbate 
80 reconstitution solution into the 60 cc NanoPac powder vial.  
• Vigorously hand shake with inversions to make sure all the particles adhering to the interior 
of the vial and stopper are wetted.  
• Continue shaking for 1 minute and examine the suspension for any large clumps of particles. 
• Immediately after shaking, use a syringe with a 27-gauge needle or larger to add 46 mL of 
0.9% sodium chloride for injection to the vial and hand shake the vial for another 1 minute. 
Periodically examine the suspension for any large visible clumps. If present, continue hand 
mixing until the suspension is properly dispersed.  
• After mixing, allow the suspension to sit undisturbed for at least 5 minutes to reduce 
entrapped air and foam. 
• The reconstituted suspension should be stored at room temperature and should be 
administered within 8 hours of suspension. DO NOT freeze or refrigerate. 
Dose withdrawal procedure: 
• At the time of dose administration, the vial should be inverted twice immediately prior to 
dose removal to ensure uniformity of the suspension. 
• Using a syringe with a 27-gauge needle or larger bore, invert the vial and insert the needle 
into the septum of the inverted vial. Withdraw just over the amount of suspension needed, 
remove the needle from the vial, and adjust to the desired volume. 
 
The withdrawn suspension will then be instilled into the peritoneal cavity immediately following 
cytoreductive surgery.  Final methodology for instillation of the NanoPac suspension will be at 
the surgeon’s discretion. The method used should minimize loss of dosing suspension from the 
peritoneal cavity and allow for the coating of the remaining intraperitoneal tumor implants (if 
any) and sites of tumor excision. One approach would be to place an indwelling catheter, close 
the incision, instill the dose suspension via the catheter, and remove the catheter. Another 
approach could be to close the incision, except for an area for an irrigation syringe which could 
be used to instill the dose suspension prior to final closure of the incision. The device used for 
instillation is at the discretion of the surgeon; however, examples of instillation devices include 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 25 of 42 
an irrigating syringe in a laparotomy and an irrigation cannula in a laparoscopic procedure. The 
device chosen must have apertures that are at least 27-gauge in diameter.  
 
8.3.2 IV Chemotherapy  
All subjects are expected to initiate IV carboplatin and IV paclitaxel treatment following 
cytoreductive surgery. IV carboplatin and IV paclitaxel will be administered, either every 21 
days or on a dose dense schedule for up to six cycles post-surgery (SOC). IV chemotherapy must 
be supplied by the investigational site and administered in accordance with institutional and 
investigator SOC. Details of the chemotherapy must be recorded in the subject’s study record 
and in the eCRF. 
The SOC is expected to remain the same for all cycles of treatment. However, the regimen can 
be modified after cycle 1 if, in the investigator’s opinion, that change is best for the subject and 
the new treatment does not involve an investigational agent. Bevacizumab may be included in 
the SOC regimen at the Investigator’s discretion, as long as it is initiated at least 6 weeks post-
surgery. Dosing and dose adjustments should be as per institutional standards. 
The IV chemotherapy regimen for this protocol is: 
• Intravenous carboplatin therapy at a dose of AUC 5 to 6 given on Day 1 of the cycle; 
• Intravenous paclitaxel at a dose of 175 mg/m2 given every 21 days, or 80 mg/m2 given 
weekly; 
• Note that in the case of allergic reaction cisplatin can be used instead of carboplatin. Dosing 
should be as per institutional standards. 
Delays in scheduled chemotherapy treatment for toxicity and recovery are permitted provided the 
delay period does not exceed 4 weeks between completion of one cycle and commencement of 
the next. If the subject requires a delay longer than 4 weeks, the Sponsor/Medical Monitor 
should be contacted for consultation as to whether or not the subject may remain on the study. 
8.3.3 Concomitant Medications and Treatments 
All medications or treatments the patient is taking at entry and through the end of the treatment 
period will be recorded in the subject’s record and the eCRF. Medications administered should 
be recorded according to the generic name when possible. Concomitant medications should be 
limited to those that are medically necessary. Any concomitant medication used should have an 
indication recorded. 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 26 of 42 
8.3.4 Prohibited, Excluded, and Contraindicated Medications and Treatments 
The following medications or treatments will be excluded during the course of the study and 
must be discontinued within the time frame indicated below before the first treatment cycle 
begins. Patients requiring these medications or treatments during the course of the study may be 
discontinued from the study. 
• Non-protocol chemotherapy, immunotherapy, radiation therapy, or anti-tumor treatment. 
• Any medication or therapy contraindicated in patients treated with paclitaxel or carboplatin 
as identified in the current version of their package inserts. 
• Exposure to any other investigational drugs within 30 days of planned instillation of 
NanoPac, with the exception of subjects participating in PARP inhibitor trials.  These 
subjects must discontinue the investigational agent prior to surgery 
9 
ADVERSE EVENT REPORTING 
9.1 
Adverse Event 
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. 
 
Adverse events occurring from the time of surgery through to the end-of-treatment visit (whether 
or not attributable to the Investigational Agent), will be recorded in the medical record and the 
eCRF. This includes AEs observed by the Investigator or reported by the subject. The following 
information will be recorded for all adverse events: 
• Name of condition/diagnosis/description 
• Onset and resolution dates 
• Severity 
• Relationship to Investigational Agent 
• Action taken 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 27 of 42 
• Seriousness  
Adverse events should be followed until resolved, stabilized or if ongoing at End-of-Study, for a 
minimum of 30 days following the termination of the subject’s participation from the study for 
any reason. 
Subjects will be required to spontaneously report any AE. Study personnel will ask open-ended 
questions to obtain information about AEs at every visit during the treatment period. Date and 
time of onset and resolution (if applicable) of the AE will be documented. 
9.1.1 Relationship to Investigational Agent 
Relationship of Adverse Events to the Investigational Agent will be classified by the Principal 
Investigator using the following definitions: 
• No relationship to Investigational Agent:  the event is not associated with Investigational 
Agent. 
• Possibly related to Investigational Agent:  the event follows a reasonable temporal 
association with the Investigational Agent administration, however could have been 
produced by the patient’s clinical condition or other therapy. 
• Probably related to Investigational Agent:  the event follows a) a reasonable temporal 
association with the Investigational Agent administration, but b) abates upon discontinuation 
of Investigational Agent and c) cannot be explained by the patient’s clinical condition or 
other therapy.  
• Definitely related to Investigational Agent:  the event: a) follows a reasonable temporal 
association with the Investigational Agent administration, but b) abates upon discontinuation 
of Investigational Agent, c) cannot be explained by the patient’s clinical condition or other 
therapy, and d) reappears on re-exposure to Investigational Agent. 
9.1.2 Severity 
Signs and symptoms will be graded by the Investigator as mild, moderate, severe, life-
threatening, or fatal according to the following definitions: 
• Mild:  Causing no limitation of usual activity 
• Moderate:  Causing some limitations of usual activities 
• Severe:  Causing inability to carry out usual activities 
• Life-Threatening:  Patient was at immediate risk of death from the event 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 28 of 42 
• Fatal:  Death related to the event. 
Toxicities and variables that are the specific endpoints of this study should be evaluated 
according to the NCI CTCAE, version 4.0. 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
Toxicity grades should be recorded as: 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Life-
Threatening, 5 = Fatal. 
9.2 
Serious Adverse Event (SAE) 
An SAE is any adverse event that meets at least one of following criteria: 
a) 
Is fatal; 
b) 
Is life-threatening, meaning the patient was, in the view of the Investigator, at immediate 
risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it 
occurred in a more serious form or progressed, might have caused death; 
c) 
Is a persistent or significant disability or incapacity; 
d) 
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); 
e) 
Is a congenital anomaly or birth defect; 
f) 
Other important medical events may be considered a serious adverse experience when, 
based upon appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes as listed in #a-e in this 
definition. 
All SAEs, including death, due to any cause which occurs during this study and until 30 days 
after the last cycle of IV chemotherapy, whether or not expected and regardless of relationship to 
the Investigational Agent, must be reported to the Sponsor immediately upon discovery of the 
event, using a US Biotest SAE reporting form, by fax and, if necessary, by phone to: 
US Biotest Medical Monitor: 
Dr. Tony Verco 
Phone: 
(805) 762-4615 
Fax: 
(805) 888-4290 
 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 29 of 42 
24-hour Emergency Contact: 
 
Peter Mast, CCRA 
 
 
Gere diZerega, MD 
Study Manager 
 
 
Medical Director 
(281) 630-6731 
 
 
(805) 630-2800 
 
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). 
All SAEs must be followed until the event resolves or, in the opinion of the Investigator, 
becomes stable. Hospitalization of patients for the administration of chemotherapy will not be 
considered an SAE. 
The Sponsor will report any serious, unexpected and drug-related adverse events to applicable 
regulatory agencies and make these reports available to the investigative sites. The Investigator 
must promptly inform the IRB of such events and retain a copy of the notification in the site’s 
regulatory binder. 
9.3 
Pregnancy 
Any pregnancy occurring while a subject is enrolled in the study or for 30 days following the last 
cycle of IV chemotherapy must be reported to US Biotest within 24 hours of the pregnancy being 
made known to the Investigator.  
10 EFFICACY AND SAFETY VARIABLES 
This is an exploratory study of the safety profile and effects on epithelial ovarian cancer of 
intraperitoneal NanoPac administered at the time of cytoreductive surgery.  
10.1 Efficacy Variables 
• CA-125 level 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 30 of 42 
• Tumor burden (residual disease) shown by imaging and calculated per RECIST (version 1.1) 
criteria 
• Progression-free survival (PFS) 
• Survival 
• Cancer-related symptoms (including bowel obstruction, ascites) 
10.2 Safety Variables 
• Adverse events 
• Laboratory assessments 
• ECOG performance status. 
11 STATISTICAL CONSIDERATIONS 
This is a prospective, multi-center, randomized, study subject-blinded Phase II study evaluating 
the safety and efficacy of NanoPac in the treatment of epithelial ovarian cancer. A detailed 
discussion of study statistical considerations will be part of the Statistical Analysis Plan (SAP), 
which will be generated and signed off after the data has been reviewed and prior to database 
lock and unblinding. 
The study will be presented descriptively as it has not been powered for inferential analysis. 
There are two stages for the trial. The goal of the first stage is to screen subjects exposed to four 
doses of IP NanoPac, escalated by 100 mg (100, 200, 300 and 400 mg/m2), instilled immediately 
post cytoreductive surgery and determine two best dose levels to move to the efficacy phase for 
further investigation. In the next stage, subjects will be randomized to one of the two chosen 
NanoPac doses plus standard of care (SOC), or SOC alone. 
 
All subjects in the trial will receive their assigned NanoPac dose (or none for those randomized 
to SOC alone) and when recovered sufficiently from surgery they will also receive up to 6 cycles 
of post-surgery IV chemotherapy.     
 
To best capture the safety profile of NanoPac, the safety data will be summarized into the 
monotherapy phase (only NanoPac) followed by the adjunctive SOC therapy phase. The efficacy 
treatment outcomes will be summarized by the NanoPac treatment received.  
 
All data will be tabulated, listed, and numbered in accordance with the ICH E3 Guidance 
document for Clinical Summary Reports. 
 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 31 of 42 
11.1 Sample Size Estimations 
Although the sample sizes were chosen clinically, retrospective calculations were performed to 
provide context for the results of the trial. In the initial dose finding stage, there would be a 
minimum of 3 subjects per dose (100, 200, 300 or 400 mg/m2). Using nQuery Advisor (version 
6.01) and the procedure confidence interval for observing a rare event it was estimated that for a 
sample size of 3, the probability of observing at least one event will be 0.834 when the 
probability of an event is 45%. For the second stage (i.e., 3 groups of 15 where the proportion of 
subjects progressing at 12 months is the event of interest), the procedure employed was the 
confidence interval for a proportion using a normal distribution. For a sample size of 15, a two-
sided 95.0% confidence interval for a single proportion using the large sample normal 
approximation will extend 0.253 from the observed proportion for an expected proportion of 
0.500.  
11.2 Populations 
All subjects who enroll in the trial and have at least one dose of study medication, basically the 
intra-surgical treatment with NanoPac, will be part of the safety and the efficacy populations. 
Subject data from the initial dose finding stage (open assignment) will be combined with the 
same dose data from the second stage as a secondary population for analysis to provide a more 
robust estimate of the treatment outcomes. 
11.3 
Missing Data 
Data will be presented as observed. No imputation will be performed for missing data. 
11.4 
Subject Disposition and Characteristics 
All subjects who enter the trial and are exposed to treatment will be accounted for. The formal 
tables and listings will focus on the randomized subjects. Subjects terminating early will be 
summarized and the reasons for termination noted. 
Subject baseline data for the dose finding and efficacy sections will be presented separately by 
dose group and also combined by dose group. This will include demography, screening 
laboratory data, medical history (which will be coded to MedDRA terms), disease history, 
relevant surgical information (e.g., extent of disease, duration of surgery, relevant biomarkers), 
and medication. 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 32 of 42 
11.5 
Primary Safety Outcome 
The primary objective of the first part of this trial is to establish safety of the four (4) treatment 
doses when instilled as part of cytoreductive surgery. Safety will provide the optimal guidance in 
defining the two best dose levels to move forward with in the next stage of the trial. 
Safety will be assessed primarily via the adverse events (AEs) recorded as these will contain any 
clinically relevant changes in the laboratory values, the vital signs, and physical examination.  
All AEs will be coded in the latest version of MedDRA. Treatment-emergent AEs for this stage, 
occur when the date and time of the AE onset is on or after the first application of the 
Investigational Agent (surgery) and any time up to when the IV therapy commences, will be 
summarized for each treatment group; an attempt will be made to determine the “within dose” 
variation between active and control, if the data are amenable. The summaries will include an 
overall summary of the number of subjects reporting and the number of events reported; 
summaries of AEs leading to termination or death; summaries by severity and relatedness – 
separately and combined – the combined display will include the subject identifier. 
Of greatest interest will be post-surgery signs of toxicity (e.g., severe abdominal pain after 5-7 
days, neutropenia, thrombocytopenia, bowel dehiscence, prolonged ileus). 
Other Stage 1 Outcomes 
Other outcomes to be reported are the radiological assessment and concomitant medication. 
11.6 
Primary Efficacy Outcome 
The second stage subjects will be randomized to one of three treatments – one of two doses of 
NanoPac from stage 1 plus standard of care (SOC), or SOC only. Subjects will be monitored 
every three months for the first 12 months and then every six months thereafter until progression 
or the last subject in the trial has been monitored for 12 months. All the monitoring information 
including biomarkers (e.g., CA-125), imaging (tumor burden) and cancer-related symptoms 
(including bowel obstruction and ascites) will be summarized in tables displaying the treatment 
group results across time. 
Progression will be presented as time to progression (i.e., Kaplan-Meier) as well as percent 
progressed up to and including 12 months post-IV chemotherapy. 
Exploratory Approach 
Factors, which will be thoroughly defined in the Statistical Analysis Plan (SAP), will be included 
in a logistic regression with progression (yes/no) at 12 months as the response. A variety of 
covariates, including treatment, will be assessed for their association with progression (e.g., 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 33 of 42 
staging, residual disease, number of IV cycles). These may be used as stratification factors in 
future trials. 
11.7 
Treatment-Related Information 
The traditional summary of the number of cycles, dose delays, and dose reductions will be 
provided for the IV part of the treatment. 
11.8 
Pharmacokinetics 
Plasma samples will be collected on Day 1 at 1, 2, 4, 8, and 24 hours post-intraperitoneal (IP) 
instillation of NanoPac if clinically feasible, and weekly thereafter until IV chemotherapy begins, 
to provide information on resulting paclitaxel systemic exposure in subjects that receive IP 
NanoPac. Additionally, a PK sample will be collected prior to each cycle of post-surgery IV 
chemotherapy, as well as at the Month 9 and Month 12 follow-up visits for determination of 
paclitaxel concentrations to assess potential NanoPac persistence. Since Day 1 predose plasma 
samples are expected to be below the limit of quantification (BLQ), predose samples will not be 
collected and paclitaxel concentrations will be reported as zero. 
Non-compartmental pharmacokinetic parameters will be calculated for paclitaxel if supported by 
the data:  
Cmax – maximum observed plasma concentration 
Tmax – time of maximum observed plasma concentration 
AUC0-last – area under the plasma concentration-time curve from time zero to time of last 
measurable concentration  
Pharmacokinetic parameters, with the exception of Tmax, will be summarized using the arithmetic 
and geometric means, standard deviation, median, range, and % CV (coefficient of variation). 
Tmax will be summarized by the median and range of its values. Plasma paclitaxel concentrations 
will be summarized using the arithmetic mean, standard deviation, coefficient of variation, 
median, and range. Graphs of Day 1 individual and mean paclitaxel concentration-time data 
following NanoPac IP instillation will be generated. After a review of the data, the SAP may 
indicate that no summarization will be performed but rather listings and displays of the 3 
subjects in each group will provide more relevant information. 
All PK sample data will be summarized descriptively and allow for clinical assessment of 
persistence (i.e., depot effect) of NanoPac. 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 34 of 42 
11.9 
Safety Outcomes 
Laboratory outcomes will be listed. Clinically significant laboratory and vital sign changes will 
be captured as AEs. 
11.10 Concomitant Medication 
Medication recorded during the trial will be coded using the most recent version of WHO Drug 
Dictionary (WHODD), summarized by anatomical system and therapeutic class in tables 
employing treatment group as a factor. 
11.11 Safety Monitoring Committee (SMC) 
The Safety Monitoring Committee (SMC) will draft and agree to a Charter which outlines the 
criteria to be applied to the subjects in the trial as well as the final choice of dose groups to be 
studied further, prior to the first subject being enrolled in the trial. The trial statistician will work 
with the SMC to produce specific data driven reports to support their decision making. 
Subject safety will be the primary driver in all decision making. 
11.12 Interim Analysis 
No interim analysis has been scheduled for this trial. 
12 DATA QUALITY ASSURANCE 
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 to attest to the accuracy, authenticity, and completeness of the data. 
The eCRF application, TrialMaster, will be licensed from OmniComm. Access to the system is 
restricted by username and password; these are controlled by the Data Management CRO, 
McDougall Scientific Ltd. 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 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 35 of 42 
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. All data, 
both eCRF and external data (e.g., laboratory data), will be entered into a clinical system. 
12.1 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 
patient’s medical records, regulatory binder, study binder, eCRFs, and source documents as 
needed to assure the conduct of the study was within compliance. In addition, the FDA or other 
government agencies may request an inspection following notification to the site. In such an 
event, the Investigator agrees to notify the Sponsor immediately of the request and will allow 
Sponsor and inspectors to review records. 
US Biotest will conduct a site initiation visit to provide the Investigator and their staff with a 
comprehensive overview of the protocol and study procedures and to review mutual obligations 
and requirements of regulatory authorities. A regulatory file or binder containing required 
documentation will be kept at the site for reference and inspection. 
Routine monitoring visits will be made to assure compliance with the study protocol, to review 
the patient’s eCRF and compare with source documents, to ensure adequate records of clinical 
supplies are maintained, and to assess the continued suitability of the investigational site. On 
completion of the study, the monitor will make a final assessment of the conduct of the study and 
inventory all clinical supplies to be returned to US Biotest. 
12.2 Source Documents 
The Investigator must maintain adequate and accurate source documents on which the eCRFs for 
each patient are based. They will be separate and distinct from the eCRFs. These records should 
include detailed notes on: 
• The medical history prior to the patient’s involvement in the study; 
• Date of informed consent; 
• The basic identifying information that links the patient’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 patient; 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 36 of 42 
• The medical condition during the patient’s involvement in the study; 
• All adverse events; 
• The patient’s exposure to the study medication; 
• The patient’s exposure to any concomitant therapy; 
• All relevant observations and data on the condition of the patient throughout the trial; 
• Justification for all entries in the patient’s eCRF.  
A log of all potentially eligible patients consented but not enrolled for obvious violations of the 
entry criteria will be kept at the site. The log will contain patients’ initials, subject number, 
diagnosis, and reason for ineligibility. 
12.3 Electronic Case Report Forms (eCRFs) 
An eCRF is required and must be completed for each consenting 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. 
12.4 Disposition of Clinical Supplies 
The Investigator will maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the Investigational Agent, including the date, quantity, batch or code number, and 
identification of patients (number, initials) who received study medication. 
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. 
13 ETHICS 
13.1 Institutional Review Board/Ethics Committee 
Before the start of the study, the study protocol, informed consent form and/or other appropriate 
documents will be submitted to the IRB and/or the authorities, in accordance with local legal 
requirements. It is the responsibility of the Investigator to assure that all aspects of the IRB 
review are conducted in accordance with current regulations. US Biotest and the Investigator 
must inform each other in writing that all ethical and legal requirements have been met before 
the first patient is enrolled in the study. 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 37 of 42 
Amendments to the protocol will be subject to the same requirements as the original protocol. 
13.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the ethical principles of the Declaration of 
Helsinki. Sponsor and Investigator will comply with their responsibilities as defined in 21 CFR 
312.50-312.70. 
13.3 Patient Information and Consent 
The Investigator will obtain informed consent from each patient enrolled in the study, in 
accordance with the U.S. Food and Drug Administration (FDA) regulations 21 CFR 50.20 - 
50.27 and the laws and regulations of the state in which the investigation is being conducted. The 
IRB must approve the Informed Consent Form (ICF) to be used by the Investigator. The 
Investigator will provide the Sponsor with a copy of the written approval generated by the IRB 
or Ethics Committee before the Investigator will be permitted to enroll subjects into the study. 
It is the responsibility of the Investigator to ensure that informed consent is obtained from the 
patient or his/her guardian or legal representative before any activity or treatment is undertaken 
which is not part of routine care. This includes, but is not limited to, the performance of 
diagnostic or therapeutic procedures and the administration of study medication. The draft 
version of the informed consent document will be modified by each site and reviewed and 
approved in writing by US Biotest prior to submission to the IRB. 
Should a protocol amendment be made, the subject consent form may be revised to reflect the 
changes of the protocol. If the consent form is revised, it is the responsibility of the Investigator 
to ensure that an amended consent is approved by the IRB and signed by all subjects currently on 
study as well as those subsequently entered in the study. 
The Investigator will not undertake any investigation specifically required only for the clinical 
study until valid consent has been obtained. The terms of the consent and when it was obtained 
must also be documented in the eCRF. The original, signed informed consent document must be 
maintained on file at the study site and be made available for review during monitoring visits and 
site audits. 
13.4 Protocol Amendments 
Any changes to this protocol may only be made in a written protocol amendment approved by 
US Biotest, the applicable regulatory agencies and the participating IRBs/Ethics Committees. 
Once the study has started, amendments will be made at the sole discretion of US Biotest.  


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 38 of 42 
The Investigator is expected to take any immediate action required for the safety of a study 
subject, even if this action results in a departure from the protocol. In such cases, the Sponsor 
and the site’s IRB should be notified of the action as soon as is reasonably possible.  
13.5 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 their patient number. The 
subjects will be told that all study findings will be stored and handled in strictest confidence, 
according to legal requirements, but will be informed that authorized research investigators and 
agents of the United States Food and Drug Administration (FDA), the National Cancer Institute, 
and authorized personnel of US Biotest have the right to inspect their medical records. 
14 STUDY ADMINISTRATIVE STRUCTURE 
14.1 Sponsor Contacts 
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 shown on the cover 
page of this protocol and will be provided to the Investigator in separate study documents. 
14.2 Maintenance of Study Records 
The Investigator must retain a copy of all study documents, including reports to the IRB and US 
Biotest in accordance with the FDA or local regulations, whichever are the more stringent. 
The Investigator must maintain study documents: 
• For a minimum of two years following the date the marketing application (NDA) is approved 
for the indication for which the drug was investigated for;  
• For a minimum of two years following the release date of the final report, if no marketing 
application is to be filed, or if the marketing application is not approved for the indication of 
which the drug was investigated or is discontinued and the FDA has been notified; or, 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 39 of 42 
• For a minimum of fifteen 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 disposing of 
any records. 
14.3 Final Report 
Upon terminating the study, the Investigator will submit a final report to the IRB and provide a 
copy to the Sponsor. This report should include any deviations from the protocol, the number 
and types of subjects evaluated, the number of subjects who discontinued, including reasons, 
results of the study, adverse events, and a conclusion summarizing the results.  
If requested by the Investigator, at the completion of the study and following analysis of the data, 
US Biotest will supply a tabulated listing of data and a final clinical statistical report.  
14.4 Publication and Use of Study Findings 
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. This will be a multicenter study. Any publication/presentation of data 
must include the entire study population. Publication/presentation of data from individual study 
centers will not be allowed without explicit permission from US Biotest. Submission of data for 
publication/presentation will be coordinated and approved by US Biotest in collaboration with 
the Investigator.  
14.5 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance coverage in accordance with 
all local legal requirements. The civil liability of the Investigator, the persons instructed by him, 
the hospital, practice, or institute in which they are employed, and the liability of the Sponsor in 
respect of financial loss due to personal injury and other damage, which may arise as a result of 
the carrying out of this study, are governed by the applicable law. As a precautionary measure, 
the Investigator, the persons instructed by him and the hospital, practice or institute are included 
in such coverage in regards to work done by them in carrying out this study to the extent that the 
claims are not covered by their own professional indemnity insurance. The Sponsor will arrange 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 40 of 42 
for subjects participating in this study to be insured against financial loss due to personal injury 
caused by the pharmaceutical products being tested or by medical steps taken in the course of the 
study. Such insurance is taken out by the Sponsor in accordance with regulations in the country 
concerned. To the extent that payments are made under such insurance, the right to claim 
damages extinguishes. 
 
 
 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 41 of 42 
15 REFERENCES 
Williamson S, Johnson G, Maulhardt H, Moore K, et al. A phase I study of intraperitoneal 
nanoparticulate paclitaxel (Nanotax®) in patients with peritoneal malignancies. Cancer Chemoth 
Pharm. 2015;75(5): 1075-1087. 
 
  
 
 


NanOlogy, LLC. 
Clinical Study Protocol 
 
NANOPAC-2016-01 
 
 
Version:  05 
19April2019 
CONFIDENTIAL 
Page 42 of 42 
APPENDIX A:  ECOG PERFORMANCE STATUS 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 self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. 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-2016-01 
 
 
Protocol Title: 
Phase II Study of Four Dose Levels of Intraperitoneal Nanopac® plus IV 
Carboplatin and Paclitaxel in Patients with Epithelial Ovarian Cancer 
Undergoing Cytoreductive Surgery 
 
 
Project Code: 
NA01NAE 
 
 
Study Phase: 
II 
 
 
Trial Design: 
3+3 dose finding phase followed by 1:1:1 randomized phase 
 
 
Study Drugs: 
Nanopac (Sterile Nanoparticulate Paclitaxel) 100, 200, 300, 400 mg/m2 
 
 
Subjects: 
Dose finding phase: Approximately 16 subjects 
Efficacy phase: Approximately 45 subjects 
 
 
Treatment Period: 
Approximately 6 months of treatment, minimum 12 months of follow-up 
 
 
Sponsor Contact: 
Leanne Drummond 
US Biotest, Inc. 
231 Bonetti Drive, Suite 240 
805-595-1300 
Leanne.drummond@usbiotest.com 
 
 
Analysis Contact: 
 
Blue Neustifter 
McDougall Scientific Ltd. 
789 Don Mills Rd, Suite 802 
Toronto, Ontario, M3C 1T5 
416-673-9478 
bneustifter@mcdougallscientific.com 
 
 
Date: 
January 29, 2020 
 
 
Status: 
Final v 1.0 
 
 
 
 


McDougall Scientific Ltd.
US Biotest, Inc.
 
 
Project Code #:  NA01NAE 
 
Protocol Number:  NANOPAC-2016-01 
Date:  January 29, 2020 
 
 
Status:  Final v 1.0 
Confidential & Proprietary 
i of iv 
Table of Contents 
1. 
List of Abbreviations Definition of Terms ......................................................................... 1 
2. 
Background .................................................................................................................... 2 
3. 
Objectives ...................................................................................................................... 2 
3.1. 
Primary Objective(s) ........................................................................................... 2 
3.2. 
Secondary Objective(s) ....................................................................................... 2 
4. 
Study Design .................................................................................................................. 3 
4.1. 
Primary Outcomes .............................................................................................. 3 
4.2. 
Secondary Outcomes ......................................................................................... 3 
4.3. 
Pharmacokinetic Outcomes ................................................................................ 3 
4.4. 
Safety Outcomes ................................................................................................ 3 
5. 
Data Management .......................................................................................................... 4 
5.1. 
Data Management .............................................................................................. 4 
5.2. 
Coding ................................................................................................................ 4 
5.3. 
Missing Data ....................................................................................................... 4 
6. 
Change to Analysis as Outlined in the Protocol .............................................................. 4 
7. 
Statistical Methods ......................................................................................................... 5 
7.1. 
Study Populations ............................................................................................... 5 
7.1.1. Safety Population .................................................................................... 5 
7.2. 
Calculated Outcomes .......................................................................................... 5 
7.3. 
Analysis Methods ................................................................................................ 5 
7.3.1. Efficacy Analyses .................................................................................... 5 
8. 
Results ........................................................................................................................... 6 
8.1. 
Study Subjects .................................................................................................... 6 
8.1.1. Patient Disposition ................................................................................... 6 
8.1.2. Patient Characteristics ............................................................................. 6 
8.2. 
Pharmacokinetic Outcomes ................................................................................ 6 
8.3. 
Safety Outcomes ................................................................................................ 7 
8.3.1. Adverse Experiences............................................................................... 7 
8.3.2. Concomitant Medication .......................................................................... 7 
8.3.3. Vital Signs ............................................................................................... 7 


McDougall Scientific Ltd.
US Biotest, Inc.
 
 
Project Code #:  NA01NAE 
 
Protocol Number:  NANOPAC-2016-01 
Date:  January 29, 2020 
 
 
Status:  Final v 1.0 
Confidential & Proprietary 
ii of iv 
8.3.4. ECOG Performance Status ..................................................................... 7 
8.3.5. Laboratory Analytes ................................................................................ 7 
8.3.6. IV Chemotherapy .................................................................................... 8 
8.3.7. CA-125 8 
8.3.8. Cancer-Related Symptoms...................................................................... 8 
 
 
 


McDougall Scientific Ltd.
US Biotest, Inc.
 
 
Project Code #:  NA01NAE 
 
Protocol Number:  NANOPAC-2016-01 
Date:  January 29, 2020 
 
 
Status:  Final v 1.0 
Confidential & Proprietary 
iii of iv 
Signature Approval Page 
1 of 2 
 
 
 
Date of Final Protocol: 
14-Jun-2016 
 
 
Amendments: 
V2 20-Oct-2016 
V3 21-Feb-2017 
V4 26-Jul-2017 
 
 
Date of Final Plan 
29-Jan-2020 
 
 
 
 
I have reviewed the Statistical Analysis Plan.  My signature below confirms my agreement with 
the contents and intent of this document. 
 
 
 
Author: 
 
 
 
 
 
 
 
 
 
Blue Neustifter 
Senior Statistician, McDougall Scientific Ltd. 
 
 
Date:  dd-mmm-yyyy 
 
 
 
Reviewed by: 
 
 
 
 
 
 
 
Hong Chen, MSc., P.Stat 
Chief Analytics Officer, 
McDougall Scientific Ltd. 
 
 
Date:  dd-mmm-yyyy 
 
 
 
 
 
 


McDougall Scientific Ltd.
US Biotest, Inc.
Project Code #:  NA01NAE
Protocol Number: NANOPAC-2016-01
Date: January 29, 2020
Status: Final v 1.0
Confidential & Proprietary
iv of iv
Signature Approval Page
2 of 2
Date of Final Protocol:
14-Jun-2016
Amendments:
V2 20-Oct-2016
V3 21-Feb-2017
V4 26-Jul-2017
Date of Final Plan
29-Jan-2020
I have reviewed the Statistical Analysis Plan. My signature below confirms my agreement with 
the contents and intent of this document.
Reviewed by:
Peter Mast
Clinical Project Manager
US Biotest
Date:  dd-mmm-yyyy
Gere diZerega, MD
Vice President for Medical Affairs
NanOlogy, LLC
Date: dd-mmm-yyyy
29 Jan 2020


McDougall Scientific Ltd.
US Biotest, Inc.
 
Project Code #:  NA01NAE  
 
Protocol Number:  NANOPAC-2016-01 
Date:  January 29, 2020 
 
 
Status:  Final v 1.0 
Confidential & Proprietary 
1 of 8 
1. 
List of Abbreviations Definition of Terms 
Abbreviation or Term 
Definition 
AE 
Adverse Event 
APR 
Analysis programming requirements 
BLQ 
Below the limit of quantification 
CA-125 
Cancer antigen 125 
CV 
Coefficient of Variation 
DLT 
Dose-limiting toxicity 
DMP 
Data management plan 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
IP 
Intraperitoneal 
MedDRA 
Medical Dictionary for Regulatory Activities (coding for AEs) 
MTD 
Maximum tolerated dose 
PFS 
Progression free survival 
PK 
Pharmacokinetic 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SDLC 
Systems development lifecycle 
SMC 
Safety Monitoring Committee 
SOC 
Standard of care 
SOP 
Standard operating procedure 
TEAE 
Treatment emergent adverse event 
 
 
 


McDougall Scientific Ltd.
US Biotest, Inc.
 
Project Code #:  NA01NAE  
 
Protocol Number:  NANOPAC-2016-01 
Date:  January 29, 2020 
 
 
Status:  Final v 1.0 
Confidential & Proprietary 
2 of 8 
2. 
Background 
NANOPAC-2016-01 is a two-part Phase II clinical trial of NanoPac suspension administered via 
intraperitoneal (IP) therapy in subjects with epithelial ovarian cancer considered appropriate for 
treatment with IV platinum and paclitaxel undergoing cytoreductive surgery. IP therapy is 
designed to expose cancer confined to the peritoneal cavity to higher concentrations of drug 
treatments for longer periods of time while reducing systemic toxicity.  
NanoPac (previously Nanotax®) was previously subject to a Phase I dose-finding trial and did 
not show unexpected systemic toxicity up to doses of 275 mg/m2 (the study maximum). 
Subjects receiving the active treatment in this study will receive the IP instillation of NanoPac at 
the time of their cytoreductive surgery and receive IV chemotherapy standard of care (SOC) 
post-surgery. Subjects randomized to control will receive IV chemotherapy SOC post-surgery. 
3. 
Objectives 
This trial of IP NanoPac suspension was planned to have two phases: a preliminary dose-
finding phase, and an efficacy phase that follows the conclusion of the dose-finding phase.  The 
study was put on hold in 2018 due to safety concern.  Subsequently. a decision was reached in 
2019 to not re-open enrollment, and so the final study did not include an efficacy phase and only 
included two doses in the dose-finding phase before study termination. 
3.1. 
Primary Objective(s) 
The primary objective of the dose-finding phase of this study is to determine the two best dose 
levels of IP NanoPac given at the time of surgery as determined by the occurrence of dose-
limiting toxicity (DLT) events.  
The primary objective of the efficacy phase of this study was to estimate the incidence of 
progression free survival (PFS) and time to progression for the first twelve months post-IV 
chemotherapy for the two doses of NanoPac determined in the dose-finding phase.  
3.2. 
Secondary Objective(s) 
Secondary objectives of this study are to: 
 
Determine the safety of IP NanoPac immediately following cytoreductive surgery 
 
Compare the duration of PFS between time-to-initial recurrence and time-to-recurrence 
following second cytoreductive surgery plus IP NanoPac in those subjects with recurrent 
cancer 
 
Determine plasma paclitaxel concentrations following IP administration of NanoPac 
 
Determine possible predictive factors for PFS to be used as stratification factors or 
covariates in subsequent studies 


McDougall Scientific Ltd.
US Biotest, Inc.
 
Project Code #:  NA01NAE  
 
Protocol Number:  NANOPAC-2016-01 
Date:  January 29, 2020 
 
 
Status:  Final v 1.0 
Confidential & Proprietary 
3 of 8 
4. 
Study Design 
NANOPAC-2016-01 is a Phase II trial with two stages planned, but with the second phase 
canceled due to early study termination.  The first, dose-finding, phase has a design based on 
3+3 designs common in oncology trials. Since the second phase is cancelled, this SAP will 
include only outcomes and data applicable to the first phase. 
During the first phase of the study, eligible subjects will be enrolled in groups of 3 to dose-
ascending cohorts of IP NanoPac at 100, 200, 300, or 400 mg/m2 plus SOC chemotherapy (a 
target of six cycles of IV carboplatin and paclitaxel, total number subject to investigator 
discretion) following a standard 3+3 design. The first cohort of 3 will be assigned to 100 mg/m2 
IP NanoPac. For each cohort, if no Dose Limiting Toxicity (DLT) events (as defined in Section 
6.1.1 of NANOPAC-2016-01 Protocol v. 4, dated 26-JUL-2017) occur, dose escalation will 
continue, and the following cohort will be assigned to a dose one level higher (e.g. from 100 
mg/m2 to 200 mg/m2). If 2 or more DLTs occur in the first cohort of 3, dose escalation will stop 
and the prior dose level will be regarded as the Maximum Tolerated Dose (MTD). If exactly 1 
DLT occurs in the first cohort at a dose, a further 3 subjects will be enrolled at the same dose 
level. If an additional 1 or more of the same DLT occurs in the second cohort, then dose 
escalation will stop and the prior dose level will be regarded as the MTD; otherwise, dose 
escalation will continue. This phase will continue until a MTD has been identified or until the top 
dose of 400 mg/m2 is applied without violating the rules for escalation. A Safety Monitoring 
Committee (SMC) will review accumulating safety data for a maximum of four weeks per subject 
prior to dose escalation and approve dose escalation or addition of a second cohort to the 
current dose level.  
4.1. 
Primary Outcomes 
The primary objective of the dose-finding portion of the study is safety, with no quantitative 
outcomes defined. Adverse Events (AEs), especially DLT events, will be the primary outcome 
variable examined.  
4.2. 
Secondary Outcomes 
The dose-finding portion of the study has no further outcome variables. 
4.3. 
Pharmacokinetic Outcomes 
Plasma samples will be taken on Day 1 at 1, 2, 4, 8, and 24 hours post IP NanoPac instillation 
(as clinically feasible), weekly thereafter until IV chemotherapy begins, and prior to each cycle of 
post-surgery IV chemotherapy.  
4.4. 
Safety Outcomes 
Safety outcomes will be measured by summaries of AEs, laboratory assessments, and 
performance status on the Eastern Cooperative Oncology Group (ECOG) Performance Status 
scale. 


McDougall Scientific Ltd.
US Biotest, Inc.
 
Project Code #:  NA01NAE  
 
Protocol Number:  NANOPAC-2016-01 
Date:  January 29, 2020 
 
 
Status:  Final v 1.0 
Confidential & Proprietary 
4 of 8 
5. 
Data Management 
5.1. 
Data Management 
Data will be collected at the sites via an electronic data capture (EDC) system.  The study-
specific application will be developed based on the protocol requirements and following the full 
Systems Development Lifecycle (SDLC).  The development and management of the trial 
application, including security and account administration, will adhere to the Standard Operating 
Procedures (SOPs) at McDougall.  All clinical research staff 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 have 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, or the Sponsor delegate, 
and any Serious Adverse Events (SAEs) reconciled with the pharmacovigilance data base 
working with the Medical Monitor. 
The data management processes are outlined in the project specific Data Management Plan 
(DMP); this and all related documentation are on file at McDougall and are identified by the 
project code NA01NAE. 
5.2. 
Coding 
The adverse experiences and medical history will be coded in MedDRA version 20.0 and signed 
off by the medical monitor.  All concomitant medication will be coded using WHO Drug (version 
C Mar 2017) and reviewed and signed off prior to data base lock. 
5.3. 
Missing Data 
Data will be presented as observed. No imputation will be performed for missing data.   
6. 
Change to Analysis as Outlined in the Protocol 
A mid-study change clarified that subjects may receive more than six cycles of post-surgery IV 
SAP language has been altered to reflect this. 
Due to study termination prior to the efficacy phase, the study outcomes and analyses outlined 
in the SAP were changed to reflect the data that will be available at database lock. Outcomes 
related to the efficacy phase of the study (including models for Progression Free Survival) have 


McDougall Scientific Ltd.
US Biotest, Inc.
 
Project Code #:  NA01NAE  
 
Protocol Number:  NANOPAC-2016-01 
Date:  January 29, 2020 
 
 
Status:  Final v 1.0 
Confidential & Proprietary 
5 of 8 
been removed and remaining outcomes have been clarified to be descriptive, with no inference 
attempted. 
7. 
Statistical Methods 
7.1. 
Study Populations 
7.1.1. 
Safety Population 
The Safety population consists of all subjects enrolled in any phase of the study who received 
study medication or were assigned to SOC-alone and underwent their cytoreductive surgery. All 
safety tables will be presented for this population.  
7.2. 
Calculated Outcomes 
The following are key endpoints derived from data captured at the sites via the EDC system.  
Complete documentation of the calculations and data manipulation required to go from the EDC 
database to the analysis database are contained in the companion document - the study 
Analysis Programming Requirements (APR). 
Baseline value: Baseline value for CA-125 is defined as the first CA-125 measurement taken 
prior to the second cycle of IV chemotherapy post-surgery. 
For other values, baseline is defined as the last measurement prior IP instillation.  
Change from Baseline: Value at time point  Baseline value 
Time in trial (days):  Date of last contact  Date of informed consent + 1 
Study Day: Study Day is calculated based on the time of IP NanoPac instillation, with the date 
of instillation/surgery as Study Day 1.  
Treatment emergent adverse event (TEAE): In the dose-finding phase, an adverse event is 
considered treatment emergent if it occurs on or after the date and time of the first application of 
IP NanoPac (i.e. surgery) and before the date and time of the start of the first IV therapy. 
7.3. 
Analysis Methods 
All calculations and analyses will be performed using SAS version 9.4 or higher resident on the 
Windows Server 2012R2 at McDougall Scientific Ltd. in Toronto Canada.  The continuous data 
will be summarized with N, mean, standard deviation, median and range, while the categorical 
data will be presented as counts and percentages (or proportions) for the descriptive displays.   
7.3.1. 
Efficacy Analyses 
For the dose-finding portion of the study, there are no analyses of efficacy. 
  


McDougall Scientific Ltd.
US Biotest, Inc.
 
Project Code #:  NA01NAE  
 
Protocol Number:  NANOPAC-2016-01 
Date:  January 29, 2020 
 
 
Status:  Final v 1.0 
Confidential & Proprietary 
6 of 8 
 
8. 
Results 
8.1. 
Study Subjects 
All data collected will be at a minimum listed.   
8.1.1. 
Patient Disposition 
All enrolled subjects that underwent their cytoreductive surgery will be summarized.  All post-
surgery early discontinuations will be summarized by the reason of discontinuation by 
stratification factors and treatment/dose. 
Treatment exposure (time in trial) will be summarized by dose cohort. 
8.1.2. 
Patient Characteristics 
8.1.2.1. 
Baseline Characteristics 
Demographic information (age, ethnicity, and race) and baseline vital signs (height, weight, 
temperature, heart rate, respiration, systolic and diastolic blood pressure) will be summarized 
for the Safety population by and dose. Subjects who select more than one race category will be 
grouped into a single race category denoted as multi-racial. Tables will also include summaries 
of the highest historical CA-125 measurement from the ovarian cancer history at screening.  
8.1.2.2. 
Medical History, Ovarian Cancer History, and Physical Examination 
A listing of the abnormal medical history will be presented by subject including year of 
onset/ended and current ongoing (Yes or No) status. The medical history terms will be tabulated 
by SOC (System Organ Class) and PT (Preferred Term) for each of the treatments.   
All results from the screening ovarian cancer history will be listed; highest historical CA-125 
measurement will also be summarized in the demographic tables (Section 8.1.2.1). 
A listing of Abnormal results from physical examinations (including gynecological, if applicable) 
are recorded as Medical History at screening and adverse experiences post-treatment. 
8.2. 
Pharmacokinetic Outcomes 
Plasma samples will be taken on Day 1 at 1, 2, 4, 8, and 24 hours post-IP instillation of 
NanoPac if clinically feasible, and weekly thereafter until IV chemotherapy begins for subjects 
that receive IP NanoPac. Additionally, IP NanoPac subjects will have PK samples taken prior to 
each cycle of IV chemotherapy.  
PK analysis will be performed and reported separately by a third party, and will not be described 
in this SAP. 


McDougall Scientific Ltd.
US Biotest, Inc.
 
Project Code #:  NA01NAE  
 
Protocol Number:  NANOPAC-2016-01 
Date:  January 29, 2020 
 
 
Status:  Final v 1.0 
Confidential & Proprietary 
7 of 8 
 
8.3. 
Safety Outcomes 
The safety profile will primarily be analysed by means of descriptive statistics and qualitative 
analysis.  All summaries and listings in the section are based on the Safety population. 
8.3.1. 
Adverse Experiences 
The adverse experiences/events reported will be summarized by treatment group using both the 
counts of subjects and the number of reports, for each SOC and PT.  The presentations will 
separate out and highlight any Serious Adverse Experiences (including deaths) and adverse 
events leading to discontinuation from the study.  
The summaries will at a minimum be: 1) the number of subjects reporting for all events; 2) the 
number of reports for all events; 3) the number of subjects reporting treatment-related events 
(probable and possible relationship); 4) the number of reports of treatment-related events. 
A by-subject listing of all adverse events will be provided. 
8.3.2. 
Concomitant Medication 
The concomitant medications will be listed by patient; the reason for the medication as well as 
the start and stop date/time will be presented.  Concomitant medications will also be tabulated 
and summarized by anatomical system and therapeutic class for each treatment group. 
8.3.3. 
Vital Signs 
Vital signs (temperature, heart rate, respiration, systolic blood pressure, and diastolic blood 
pressure) and body measurements (weight and height) will be summarized as mean values with 
variance, including the change from baseline, by treatment dosage. 
8.3.4. 
ECOG Performance Status 
The Eastern Cooperative Oncology Group (ECOG) Performance Status scale is administered to 
subjects at screening and the end-of-treatment visit. The ECOG scale is a 6-point scale for 
-
active, able to carry on all pre-
 
Screening and end-of-treatment results will be summarized as incidence of each rating by dose 
at each of the two assessments.  
8.3.5. 
Laboratory Analytes 
Haematology and biochemistry data will be presented as mean values with variability and 
change (absolute and relative) from baseline in each laboratory parameters. 
Results for urinalysis visit will be summarized by dose cohort. 


McDougall Scientific Ltd.
US Biotest, Inc.
 
Project Code #:  NA01NAE  
 
Protocol Number:  NANOPAC-2016-01 
Date:  January 29, 2020 
 
 
Status:  Final v 1.0 
Confidential & Proprietary 
8 of 8 
8.3.6. 
IV Chemotherapy 
Drugs administered as part of SOC IV chemotherapy will be fully listed separately from 
concomitant medications by subject and IV cycle. 
For each treatment, a summary of the number of subjects completing each IV chemotherapy 
cycle will be provided.  
8.3.7. 
CA-125 
Descriptive statistics of CA-125 will be provided by dose and assessment visit. Listings of CA-
125 by subject and assessment will contain a flag indicating if measurement is twice that of 
baseline.  
8.3.8. 
Cancer-Related Symptoms 
Incidence of cancer-related symptoms will be provided by dose for the Safety population. 
Cancer-related symptoms will be determined by medical monitor.