Conditions: Bladder Cancer Urothelial Carcinoma Urinary Bladder Neoplasm Urinary Bladder Cancer Urogenital Neoplasms Urologic Neoplasms Urologic Cancer Malignant Tumor of the Urinary Bladder Cancer of the Bladder
Keywords: non-muscle invasive bladder cancer muscle invasive bladder cancer high-risk bladder cancer BCG-unresponsive bladder cancer BCG failure BCG-refractory bladder cancer BCG-resistant bladder cancer NMIBC MIBC
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 36
Healthy volunteers: no

Brief summary:
This is a clinical trial studying the administration of NanoDoce as a direct injection to the bladder wall immediately after tumor resection and as an intravesical instillation. All participants will receive NanoDoce, and will be evaluated for safety and tolerability, as well as the potential effects of NanoDoce on urothelial carcinoma.

Detailed description:
In this clinical trial, subjects with high-risk non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC), will receive NanoDoce. Subjects will be stratified into two treatment groups, Group 1 (NMIBC) and Group 2 (MIBC). All subjects will receive NanoDoce injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT), followed by an initial NanoDoce intravesical instillation.

Once the TURBT resection site is healed (approximately 1 month), Group 1 (NMIBC) subjects will proceed to a 3-month Induction period (6 weekly NanoDoce intravesical instillations, followed by 6 weeks of rest). After the Induction period, following confirmation of non-recurrence, Group 1 subjects will proceed to a 3-month Maintenance period (3 weekly NanoDoce intravesical instillations, followed by 9 weeks of rest).

After NanoDoce direct injection and the initial intravesical instillation, Group 2 subjects will proceed to institutional standard of care and will not receive Induction or Maintenance intravesical instillations.

Arms:
arm 1: Subjects will be enrolled in sequential, dose escalating cohorts of NanoDoce direct injection (0.75, 1.5, 2.5, or 3.75 mg/mL). Subjects will also receive an initial NanoDoce intravesical instillation at 2.0 or 3.0 mg/mL and additional Induction (6 weekly NanoDoce intravesical instillations, followed by 6 weeks of rest) and Maintenance (3 weekly NanoDoce intravesical instillations, followed by 9 weeks of rest) instillations at 2.0 or 3.0 mg/mL. arm 2: Subjects will be enrolled in sequential, dose escalating cohorts of NanoDoce direct injection (0.75, 1.5, 2.5, or 3.75 mg/mL). Subjects will also receive an initial NanoDoce intravesical instillation at 2.0 or 3.0 mg/mL. Subjects will then go on to receive institutional standard of care.

Interventions: intervention 1: NanoDoce (direct injection) intervention 2: NanoDoce (intravesical instillation) - Visit 2 Instillation intervention 3: Institutional Standard of Care intervention 4: NanoDoce (intravesical instillation) - Induction and Maintenance Instillations
Intervention descriptions: intervention 1: Subjects will receive NanoDoce injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT) intervention 2: All subjects will receive an initial intravesical instillation within 2 hours of direct injection. intervention 3: Group 2 (MIBC) will receive institutional standard of care treatments after the Visit 2 intravesical instillation. intervention 4: Group 1 (NMIBC) will receive intravesical instillations in an Induction Period and a Maintenance Period.

Protocol document:
Prot_000.pdf: 
Phase 1/2 NanoDoce® Trial in Subjects with Urothelial Carcinoma 
 
Version 7.0 
NANODOCE-2017-02 
18 June 2020 
 
US Biotest, Inc. 
CONFIDENTIAL 
Page 1 of 62 
  
   
 
 
Phase 1/2 Trial Evaluating the Safety and Tolerability of 
NanoDoce® Injection and Intravesical Instillation in 
Subjects with Urothelial Carcinoma 
 
Protocol Identifying Number: NANODOCE-2017-02 
Principal Investigator: Donald Lamm, MD, FACS 
IND Sponsor: NanOlogy, LLC 
IND #: 137404 
Version Number: 7.0 
18 June 2020 
 
 
 
 
 
 
 


Phase 1/2 NanoDoce® Trial in Subjects with Urothelial Carcinoma 
 
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Table of Contents 
  
LIST OF ABBREVIATIONS ....................................................................................................................................... 5 
SPONSOR SIGNATURE PAGE ............................................................................................................................... 7 
STATEMENT OF COMPLIANCE ............................................................................................................................. 8 
PROTOCOL SUMMARY ........................................................................................................................................... 9 
Figure 1: Cohort Schedule – Group 1 – NMIBC ................................................................................................... 12 
Figure 2: Cohort Schedule – Group 2 – MIBC...................................................................................................... 13 
1 
KEY ROLES .................................................................................................................................................. 14 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................... 16 
2.1 
Background Information .................................................................................................................... 16 
2.2 
Rationale ............................................................................................................................................. 18 
2.3 
Potential Risks and Benefits ............................................................................................................ 19 
2.3.1 
Known Potential Risks ................................................................................................... 19 
2.3.2 
Known Potential Benefits .............................................................................................. 19 
3 
OBJECTIVES AND PURPOSE .................................................................................................................. 19 
4 
STUDY DESIGN AND ENDPOINTS ......................................................................................................... 19 
4.1 
Description of the Study Design ...................................................................................................... 19 
4.2 
Endpoints ............................................................................................................................................ 21 
4.2.1 
Primary Endpoint ............................................................................................................ 21 
4.2.2 
Secondary Endpoints .................................................................................................... 21 
4.2.3 
Exploratory Endpoints ................................................................................................... 21 
5 
STUDY ENROLLMENT AND WITHDRAWAL ......................................................................................... 21 
5.1 
Participant Inclusion Criteria ............................................................................................................ 21 
5.2 
Participant Exclusion Criteria ........................................................................................................... 22 
5.3 
Strategies for Recruitment and Retention ...................................................................................... 22 
5.4 
Participant Withdrawal or Termination ............................................................................................ 23 
5.4.1 
Reasons for Withdrawal or Termination ..................................................................... 23 
5.4.2 
Handling of Participant Withdrawals or Termination ................................................. 23 
5.5 
Premature Termination or Suspension of Study ........................................................................... 23 
6 
STUDY DRUG .............................................................................................................................................. 24 
6.1 
Study drug(s) and Control Description ........................................................................................... 24 
6.1.1 
Acquisition ....................................................................................................................... 24 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 24 
6.1.3 
Product Storage and Stability ....................................................................................... 25 
6.1.4 
Preparation ...................................................................................................................... 26 
6.1.5 
Dosing and Administration ............................................................................................ 26 
6.1.6 
Route of Administration ................................................................................................. 27 
6.1.7 
Starting Dose and Dose Escalation Schedule ........................................................... 27 
6.1.8 
Dose Adjustments/Modifications/Delays .................................................................... 30 
6.1.9 
Duration of Therapy ....................................................................................................... 30 
6.1.10 
Tracking of Dose ............................................................................................................ 30 
6.1.11 
Device Specific Considerations ................................................................................... 30 
6.2 
Study drug Accountability Procedures............................................................................................ 30 
7 
STUDY PROCEDURES AND SCHEDULE .............................................................................................. 31 
7.1 
Study Procedures/Evaluations ......................................................................................................... 31 


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7.1.1 
Study Specific Procedures ............................................................................................ 31 
7.1.2 
Standard of Care Study Procedures ........................................................................... 31 
7.2 
Laboratory Procedures/Evaluations ................................................................................................ 32 
7.2.1 
Clinical Laboratory Evaluations .................................................................................... 32 
7.2.2 
Other Assays or Procedures ........................................................................................ 32 
7.3 
Study Schedule .................................................................................................................................. 33 
7.3.1 
Screening (Visit 1) .......................................................................................................... 33 
7.3.2 
Trans Urethral Resection of Bladder Tumor (Visit 2) ................................................ 34 
7.3.3 
NanoDoce Treatment - Injection & Intravesical Instillation (Visit 2 continued) ..... 34 
7.3.4 
Visit 3 
35 
7.3.5 
Induction Period (Visits 4 – 9) ...................................................................................... 35 
7.3.6 
Maintenance Period (Visits 10 – 12) ........................................................................... 36 
7.3.7 
End of Treatment ........................................................................................................... 37 
7.3.8 
Safety Assessment Visit................................................................................................ 38 
7.3.9 
Early Termination Visit .................................................................................................. 38 
7.3.10 
SURVIVAL/PROGRESSION FOLLOW-UP ............................................................... 38 
7.3.11 
Unscheduled Visits ........................................................................................................ 38 
7.3.10 
Schedule of Events Table ............................................................................................. 39 
7.4 
Justification for Sensitive Procedures ............................................................................................. 43 
7.5 
Concomitant Medications, Treatments, and Procedures ............................................................. 43 
7.6 
Precautionary Medications, Treatments, and Procedures .......................................................... 43 
7.7 
Prohibited Medications, Treatments, and Procedures ................................................................. 43 
7.8 
Prophylactic Medications, Treatments, and Procedures ............................................................. 43 
7.9 
Rescue Medications, Treatments, and Procedures ..................................................................... 44 
7.10 
Participant Access to Study drug At Study Closure...................................................................... 44 
8 
ASSESSMENT OF SAFETY ...................................................................................................................... 44 
8.1 
Specification of Safety Parameters ................................................................................................. 44 
8.1.1 
Definition of Adverse Events (AE) ............................................................................... 45 
8.1.2 
Definition of Serious Adverse Events (SAE) .............................................................. 45 
8.1.3 
Definition of Unanticipated Problems (UP) ................................................................. 45 
8.2 
Classification of an Adverse Event ................................................................................................. 45 
8.2.1 
Severity of Event ............................................................................................................ 45 
8.2.2 
Relationship to Study drug............................................................................................ 46 
8.2.3 
Expectedness ................................................................................................................. 46 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up .......................................... 47 
8.4 
Reporting Procedures ....................................................................................................................... 47 
8.4.1 
Adverse Event Reporting .............................................................................................. 47 
8.4.2 
Serious Adverse Event Reporting ............................................................................... 47 
8.4.3 
Unanticipated Problem Reporting ................................................................................ 48 
8.4.4 
Events of Special Interest ............................................................................................. 48 
8.4.5 
Reporting of Pregnancy ................................................................................................ 48 
8.5 
Study Halting Rules ........................................................................................................................... 48 
8.6 
Safety Oversight ................................................................................................................................ 49 
9 
CLINICAL MONITORING ............................................................................................................................ 49 
10 
STATISTICAL CONSIDERATIONS .......................................................................................................... 50 
10.1 
Statistical and Analytical Plans ........................................................................................................ 50 


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10.2 
Statistical Hypotheses ....................................................................................................................... 50 
10.3 
Analysis Datasets .............................................................................................................................. 50 
10.3.1 
Missing Data ................................................................................................................... 50 
10.4 
Description of Statistical Methods ................................................................................................... 50 
10.4.1 
General Approach .......................................................................................................... 50 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 50 
10.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 51 
10.4.4 
Safety Analyses .............................................................................................................. 51 
10.4.5 
Adherence and Retention Analyses ............................................................................ 52 
10.4.6  
Baseline Descriptive Statistics ..................................................................................... 52 
10.4.7 
Planned Interim Analyses ............................................................................................. 52 
10.4.8 
Additional Sub-Group Analyses ................................................................................... 53 
10.4.9 
Multiple Comparison/Multiplicity................................................................................... 53 
10.4.10 
Tabulation of Individual Response Data ..................................................................... 53 
10.4.11 
Exploratory Analyses ..................................................................................................... 53 
10.4.12 
Concomitant Medication................................................................................................ 53 
10.5 
Sample Size ....................................................................................................................................... 54 
10.6 
Measures to Minimize Bias .............................................................................................................. 54 
10.6.1 
Enrollment/ Randomization/ Masking Procedures .................................................... 54 
10.6.2 
Evaluation of Success of Blinding ............................................................................... 54 
10.6.3 
Breaking the Study Blind/Participant Code ................................................................ 54 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................... 54 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................................. 55 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................... 55 
13.1 
Ethical Standard ................................................................................................................................. 55 
13.2 
Institutional Review Board ................................................................................................................ 55 
13.3 
Informed Consent Process ............................................................................................................... 56 
13.3.1 
Consent/Assent and Other Informational Documents Provided to Participants ... 56 
13.3.2 
Consent Procedures and Documentation .................................................................. 56 
13.4 
Participant and Data Confidentiality ................................................................................................ 56 
13.4.1 
Research Use of Stored Human Samples, Specimens or Data ............................. 57 
13.5 
Future Use of Stored Specimens .................................................................................................... 57 
14 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 57 
14.1 
Data Collection and Management Responsibilities ...................................................................... 57 
14.2 
Study Records Retention .................................................................................................................. 58 
14.3 
Protocol Deviations............................................................................................................................ 58 
14.4 
Publication and Data Sharing Policy ............................................................................................... 58 
15 
STUDY ADMINISTRATION ........................................................................................................................ 59 
15.1 
Study Leadership ............................................................................................................................... 59 
16 
CONFLICT OF INTEREST POLICY .......................................................................................................... 59 
17  
LIABILITY AND INSURANCE .................................................................................................................... 59 
18  
LITERATURE REFERENCES.................................................................................................................... 60 
APPENDIX A: ECOG Performance Scale ............................................................................................................ 62 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Transaminase 
BCG 
Bacillus Calmette–Guérin 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Comprehensive Metabolic Panel 
CO2 
Carbon Dioxide 
CR 
Complete Response 
CRO 
Clinical Research Organization 
CT 
Computed Tomography Scan 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture System 
eCRF 
Electronic Case Report Form 
EMR 
Electronic Medical Record 
FDA 
The U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
IT 
Intratumoral 
ITV 
Intravesical 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 


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MedDRA 
Medical Dictionary for Regulatory Activities 
MIBC 
Muscle Invasive Bladder Cancer 
MFD 
Maximum Feasible Dose 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NDA 
New Drug Application (Marketing Application) 
NF 
National Formulary 
NMIBC 
Non-Muscle Invasive Bladder Cancer 
NOAEL 
No-Adverse Effect Level 
OS 
Overall Survival 
PCA 
Precipitation with Compressed Antisolvents 
PFS 
Progression-free Survival 
pH 
Potential of Hydrogen  
PI 
Principal Investigator 
PK 
Pharmacokinetics 
Plt 
Platelet 
PT 
Prothrombin time 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDLC 
Systems Development Life Cycle 
SOC 
Standard of Care 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent Adverse Event 
TURBT 
Trans-urethral resection of bladder tumor 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
USP 
United States Pharmacopeia 
UTI 
Urinary Tract Infection 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 
 
 


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SPONSOR SIGNATURE PAGE 
Protocol Title: 
Phase 1/2 Trial Evaluating the Safety and Tolerability of NanoDoce® Injection and 
Intravesical Instillation in Subjects with Urothelial Carcinoma 
Protocol Number: 
NANODOCE-2017-02 
Version Number:  
7.0 
Date: 
 
18 June 2020 
IND Number: 
 
137404 
Investigational Product: NanoDoce (sterile nanoparticulate docetaxel) Powder for Suspension 
Sponsor: 
 
NanOlogy, LLC 
 
231 Bonetti Dr., Suite 240 
 
San Luis Obispo, CA 93401-7310 
 
805-595-1300 
The Sponsor for IND 137404, NanOlogy, LLC, has transferred responsibility for all obligations set forth in 21 CFR Part 
312 to US Biotest, Inc., with regard to the IND; in accordance with 21 CFR Part 312, US Biotest, Inc., shall be 
considered the sponsor with regard to all activities related to the IND. 
 
 
 - Name and Title: 
Gere diZerega, MD 
President & CEO, US Biotest, Inc. 
 
__________________________________________  
__________________________ 
 
 
 
Date 
 


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STATEMENT OF COMPLIANCE 
I have read the attached protocol and agree to comply with the contents of this document. 
I agree to comply with applicable FDA regulations and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. 
This document is a confidential communication of US Biotest, Inc. The recipient agrees that no unpublished 
information contained herein will be published or disclosed without prior written permission of US Biotest. However, 
this document may be disclosed to appropriate institutional review boards, ethics review committees, or authorized 
representatives of the Investigator or of boards of health under the condition that they are requested to respect the 
confidentiality of the document. 
The signature of the Principal Investigator below constitutes his/her agreement. 
 
 
__________________________________________ __________________________ 
Signature of Principal Investigator  
 
Date 
 
 
__________________________________________ 
Printed Name of Principal Investigator 
 
 


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PROTOCOL SUMMARY 
Title: 
Phase 1/2 Trial Evaluating the Safety and Tolerability of NanoDoce® Injection and Intravesical 
Instillation in Subjects with Urothelial Carcinoma 
 
 
Précis: 
In this open-label, dose rising, phase 1/2 trial, subjects with high-risk non-muscle invasive 
bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC), will receive NanoDoce 
(sterile nanoparticulate docetaxel) Powder for Suspension as a direct injection to the bladder 
wall and intravesical instillation(s). Subjects will be stratified into two treatment groups, 
Group 1 (NMIBC) and Group 2 (MIBC). At Visit 2, all subjects will receive NanoDoce injected 
into the index tumor resection site on the bladder wall, immediately following transurethral 
resection of the bladder tumor (TURBT), followed by an initial NanoDoce intravesical 
instillation (within 2 hours of the direct injection).  
Group 1 (NMIBC) and Group 2 (MIBC) Subset 
Subjects will be assessed for recovery (TURBT resection site healing) at Visit 4, at which point 
the Investigator will evaluate subject symptoms, pathology (if available), gross hematuria or 
urinalysis findings. If the Investigator determines that the subject has sufficiently recovered, 
the subject will enter a 3-month Induction period. If the Investigator determines that the 
subject has not recovered at Visit 4, evaluations will be repeated at least every 2 weeks until 
the subject has recovered and moves forward to the induction period. 
The 3-month Induction period will consist of 6 weekly NanoDoce intravesical instillations, 
followed by 6 weeks of rest. After the Induction period, subjects will proceed to a 3-month 
Maintenance period, consisting of 3 weekly NanoDoce intravesical instillations, followed by 9 
weeks of rest. Subjects will return at Visit 13 for the End of Treatment visit. Any subject 
terminating early will be required to complete all End of Treatment assessments. An 
additional Safety visit will be required 45 days after the last administration of NanoDoce if 
the End of Treatment visit is not conducted. 
Progression, progression-free survival (PFS) and post-study concomitant therapy will be 
collected at 9 and 12 months following the Day 1 NanoDoce injection for subjects who have 
retained their bladders (non-cystectomy subjects). 
Subjects will be evaluated for tumor recurrence or disease progression with cystoscopy and 
urine cytology at Visit 10, End of Treatment, or at any time, at the discretion of the 
Investigator. Biopsy is to be performed at any time at the discretion of the Investigator for 
positive or suspicious cytology or cystoscopic findings. Subjects will be followed through End 
of Treatment visit for safety, PFS and tumor response to therapy. Institution pathology data 
will be collected for any resection, cystectomy or biopsy specimen (to include, but not limited 
to bladder resection, cystectomy or node tissue) at any time during the study or early 
withdrawal.   
Group 2 (MIBC) 
At the end of Visit 3, Group 2 (MIBC) subjects will proceed to institutional standard of care 
treatments and return for the End of Treatment study visit 45 days (+/- 5 days) after Visit 2. 


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At Visit 3, a subset of subjects, as determined by the treating investigator, who are deemed 
ineligible for cystectomy and intolerant to existing standard of care chemotherapy or 
treatment, may be offered intravesical chemotherapy in the Induction and Maintenance 
periods as described for Group 1 in this study (referred to hereafter as the “Group 2 Subset”).  
Progression, PFS and post-study concomitant therapy will be collected at 6, 9 and 12 months 
following the Day 1 NanoDoce injection, for subjects who have retained their bladders (non-
cystectomy subjects). 
Groups 1 and 2 
The study will consist of a dose escalation phase and a dose confirmation phase for the direct 
injection of NanoDoce concentrations (0.75, 1.5, 2.5, or 3.75 mg/mL) for Groups 1 and 2. In 
the direct injection dose escalation phase, subjects will be enrolled in sequential cohorts of 
three subjects starting at the lowest concentration.  
The study will also dose escalate Groups 1 and 2 for the intravesical instillation of NanoDoce 
concentrations (2.0 and 3.0 mg/mL). In the intravesical instillation dose escalation phase, all 
subjects in Group 1 will be enrolled at the lowest concentration of 2.0 mg/mL for the Visit 2 
instillation. If the dose is well-tolerated, Group 1 subjects will continue to receive 2.0 mg/mL 
until Induction visit #6, then escalate to 3.0 mg/mL intravesical instillations for the 
subsequent Induction and Maintenance intravesical instillations. Group 2 subjects will be 
enrolled at the lowest concentration of 2.0 mg/mL for the Visit 2 instillation for all Direct 
Injection doses. If the dose is well-tolerated, Group 2 subjects will escalate to 3.0 mg/mL 
intravesical instillations for the dose confirmation portion of the study. For the subset of 
Group 2 subjects proceeding to the Induction and Maintenance regimen, intravesical 
instillation escalation to 3.0 mg/mL will also be determined after Visit 6.  
Following Data Safety Monitoring Board (DSMB) review of the cohort data, with the 
exception of the PK data, the DSMB will determine whether to: (a) escalate to the next dose 
level cohort (no DLT); (b) add three additional subjects to the current cohort (one DLT); (c) if 
still at the first cohort, stop the study (2 or more DLT); (d) if at higher cohorts, return to the 
previous (lower) dose cohort and expand by three subjects (more than one DLT). The dose 
determined to be most suitable for further evaluation, defined as the highest dose with an 
acceptable safety and tolerability profile (as determined by the DSMB) will enroll additional 
subjects to total up to 9 subjects at that direct injection dose level.  
Objectives: 
 
Primary objective: 
• 
To evaluate the safety and tolerability of NanoDoce injected directly into the 
bladder wall and instilled intravesically. 
 
 
Secondary objectives:  
• 
To characterize the PK of docetaxel when injected directly into the bladder wall, in 
the presence of NanoDoce intravesical instillation. 
• 
To determine whether any of the NanoDoce concentrations (0.75, 1.5, 2.5, or 3.75 
mg/mL) in the presence of NanoDoce intravesical instillation concentration dose of 
2.0 or 3.0 mg/mL, shows signs of preliminary efficacy. 
 
Endpoints: 
Primary endpoint: Safety and tolerability as demonstrated by adverse events (AE), changes in 
laboratory assessments, physical examination findings and vital signs. 


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Secondary endpoints: 
• 
Concentration of docetaxel in the systemic circulation post-injection, in the 
presence of intravesical instillation (as determined by PK analysis); 
• 
PFS defined as tumor recurrence or disease progression at Visit 10 and Visit 13;  
• 
Overall survival (OS) determined by survival time up to 12 months following Visit 4. 
 
Population: 
Group 1: Up to 42 subjects with NMIBC; 
Group 2: Up to 33 subjects with MIBC. 
 
Phase: 
Phase 1/2 
 
Number of 
Sites enrolling 
participants: 
Five 
Description of 
Study Drug: 
NanoDoce (sterile nanoparticulate docetaxel) Powder for Suspension at concentrations of 
0.75 1.5, 2.5, or 3.75 mg/mL administered by direct injection; 2.0 mg/mL or 3.0 mg/mL 
administered by intravesical instillation. 
 
Study Duration: 
Up to 30 months. 
 
Participant 
Duration: 
Group 1: Estimated up to 33 weeks, including safety assessments. 
Group 2: Estimated up to 64 days, including safety assessments. 
Group 2 Subset: Estimated up to 33 weeks, including safety assessments. 
Data collection only: at 6 (Group 2), 9 and 12 months. 
 
 
 


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FIGURE 1: COHORT SCHEDULE – GROUP 1 – NMIBC 
 
 
 
 
 
 
 
 
 
 
 
              
 
 
0.75 mg/mL DI 
2.0 mg/mL ITV 
+3 Subjects 
0 DLT 
0 DLT 
0 DLT 
0 DLT 
≥ 2 DLT 
≥ 2 DLT 
1 DLT 
1 DLT 
+1 DLT 
+1 DLT 
ITV #4 
+3 Subjects 
Enroll up to 9 total subjects at maximum tolerated dose 
0 DLT 
0 DLT 
≥ 2 DLT 
1 DLT 
+1 DLT 
DOSE CONFIRMATION PHASE 
STOP 
0.75 mg/mL DI 
3.0 mg/mL ITV 
0.75 mg/mL DI 
2.0 mg/mL ITV 
+3 Subjects 
0.75 mg/mL DI 
3.0 mg/mL ITV 
0 DLT 
≥ 2 DLT 
+1 DLT 
+3 Subjects 
1.5 mg/mL DI 
2.0 mg/mL ITV 
0 DLT 
1 DLT 
1.5 mg/mL DI 
2.0 mg/mL ITV 
ITV #4 
1.5 mg/mL DI 
3.0 mg/mL ITV 
+3 Subjects 
1.5 mg/mL DI 
3.0 mg/mL ITV 
+3 Subjects 
2.5 mg/mL DI 
2.0 mg/mL ITV 
+3 Subjects 
1 DLT 
≥ 2 DLT 
+1 DLT 
ITV #4 
2.5 mg/mL DI 
3.0 mg/mL ITV 
2.5 mg/mL DI 
2.0 mg/mL ITV 
+3 Subjects 
+3 Subjects 
3.75 mg/mL DI 
2.0 mg/mL ITV 
1 DLT 
≥ 2 DLT 
+1 DLT 
2.5 mg/mL DI 
3.0 mg/mL ITV 
+3 Subjects 
3.75 mg/mL DI 
3.0 mg/mL ITV 
≥ 2 DLT 
+1 DLT 
1 DLT 
3.75 mg/mL DI 
2.0 mg/mL ITV 
+3 Subjects 
3.75 mg/mL DI 
3.0 mg/mL ITV 
0 DLT 
0 DLT 
0 DLT 
ITV #4 
0 DLT 
0 DLT 
0 DLT 
0 DLT 
0 DLT 
≥ 2 DLT 
+1 DLT 
1 DLT 
DOSE ESCALATION PHASE 
GROUP 1 - NMIBC 


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FIGURE 2: COHORT SCHEDULE – GROUP 2 – MIBC 
 
 
 
 
0.75 mg/mL DI 
2.0 mg/mL ITV 
+3 Subjects 
STOP 
1.5 mg/mL DI 
2.0 mg/mL ITV 
+3 Subjects 
2.5 mg/mL DI 
2.0 mg/mL ITV 
+3 Subjects 
3.75 mg/mL DI 
2.0 mg/mL ITV 
+3 Subjects 
0.75 mg/mL DI 
2.0 mg/mL ITV 
1.5 mg/mL DI 
2.0 mg/mL ITV 
2.5 mg/mL DI 
2.0 mg/mL ITV 
+3 Subjects 
3.75 mg/mL DI 
2.0 mg/mL ITV 
3.75 mg/mL DI 
3.0 mg/mL ITV 
0 DLT 
0 DLT 
0 DLT 
0 DLT 
0 DLT 
0 DLT 
0 DLT 
0 DLT 
0 DLT 
1 DLT 
1 DLT 
1 DLT 
1 DLT 
1 DLT 
≥ 2 DLT 
≥ 2 DLT 
≥ 2 DLT 
≥ 2 DLT 
≥ 2 DLT 
+1 DLT 
+1 DLT 
+1 DLT 
+1 DLT 
+1 DLT 
Enroll up to 9 total Group 2/Group 2 subset 
subjects at MTD dose 
DOSE CONFIRMATION PHASE 
DOSE ESCALATION PHASE 
GROUP 2 - MIBC 
+3 Subjects 
+3 Subjects 
+3 Subjects 
+3 Subjects 
3.75 mg/mL DI 
3.0 mg/mL ITV 
0 DLT 


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1 
KEY ROLES 
Medical Director 
Gere diZerega, MD 
President & CEO, US Biotest, Inc. 
Professor, USC Keck School of Medicine 
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-630-2800 
gere.dizerega@usbiotest.com 
Study Manager 
Rose Marie Cavanna-Mast, RT CCRA 
US Biotest, Inc.  
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-595-1300 
rosemarie.cavanna@usbiotest.com 
Principal Investigator 
Donald Lee Lamm, MD, FACS 
President, BCG Oncology  
Clinical Professor 
University of Arizona College of Medicine 
3815 E Bell Rd Ste 1210 
Phoenix, AZ 85032 
dlamm@bcgoncology.com 
Medical Monitor 
Antony Verco, MD 
US Biotest, Inc.  
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-235-9193 
tony.verco@usbiotest.com 
Laboratory – PK Samples 
Covance Madison Laboratories Bioanalytical (BA) Group  
3301 Kinsman Blvd, Madison, WI 53704 
608-442-8200 
Laboratory – IHC Samples 
NeoGenomics Laboratories Inc. 
Pharma Services Department 
31 Aliso Viejo, CA 92656 
949-445-7300 Ext 7103 
 


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2  INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
2.1 
BACKGROUND INFORMATION  
The Sponsor for IND 137404, NanOlogy, LLC (NanOlogy), has transferred responsibility for all obligations set forth in 
21 CFR Part 312 to US Biotest, Inc. (US Biotest), with regard to the IND. In accordance with 21 CFR Part 312, US 
Biotest, Inc., shall be considered the sponsor with regard to all activities related to the IND. Therefore, references to 
“Sponsor” hereafter in this protocol refer to US Biotest, Inc.  
Name and description of study drug: 
NanOlogy, LLC has produced a formulation of nanoparticulate docetaxel, identified as NanoDoce® (sterile 
nanoparticulate docetaxel) Powder for Suspension (NanoDoce). NanoDoce is manufactured using a Precipitation with 
Compressed Antisolvent (PCA) technique that employs supercritical carbon dioxide and acetone to generate 
docetaxel nanoparticles within a well-characterized particle-size distribution. Following PCA, NanoDoce is filled into a 
clear 60mL Type 1, USP, clear-glass vial (100 mg/vial) as a powder fill of nanoparticulate docetaxel, closed with a 
bromobutyl rubber stopper and aluminum crimp seal, and sterilized by gamma irradiation. Prior to administration, 
NanoDoce will be reconstituted with Sterile Reconstitution Solution (1% Polysorbate 80 and 8% Ethanol in 0.9% 
Sodium Chloride for Injection, USP), to form a suspension. The suspension will be further diluted with different 
volumes of 0.9% Sodium Chloride for Injection, USP to achieve the final dose formulations. The reconstitution and 
dilution will be performed at the investigation site pharmacy. 
Nonclinical Summary: 
NanOlogy conducted one in vivo nonclinical pharmacology study to determine the effects of intratumoral (IT) 
injection of NanoDoce on a urinary bladder transitional cell carcinoma subcutaneous xenograft in an 
immunocompromised nude mouse model. The objective of Study D-PBl-02-2017, Effect of IT administered NanoDoce 
on growth of Subcutaneous (SC) UM-UC-3 Bladder Cancer in Immunocompromised (Hsd:Athymic Nude-Foxn1nu nude) 
Mice, was to evaluate the effect of one, two, or three weekly IT administrations of NanoDoce (100 mg/kg) on tumor 
growth in comparison to IT vehicle and intravenous (IV) chemotherapy (docetaxel; 30 mg/kg) controls. Treatment 
outcome was based on differences in tumor volume. Two or three weekly IT NanoDoce administrations were more 
effective than IV docetaxel in inhibiting the progression of urinary bladder carcinoma. Systemic toxicity leading to 
weight loss occurred in animals treated with three cycles of IV docetaxel or three cycles of IT NanoDoce; one or two 
cycles of IT NanoDoce did not affect weight gain. Evaluation of tissue from the tumor sites showed that IT 
administration of NanoDoce provided appreciable docetaxel levels for durations of up to 44 days following 
administration. 
NanOlogy conducted two in vivo nonclinical pharmacology study to determine the effects of NanoDoce on renal cell 
carcinoma. The objective of Study PD-Pre-03-2018, A drug efficacy study in the Sprague-Dawley Rag2; Il2rg null (SRG) 
rat xenograft model of Human renal cell Adenocarcinoma (786-O), was to evaluate the effect of one, two, or three 
weekly IT administrations of NanoDoce (20 mg/kg) on tumor growth in comparison to IT vehicle and IV 
chemotherapy (docetaxel; 2.5-5 mg/kg) controls. Treatment outcome was based on differences in tumor volume. 
One, two, and three weekly IT NanoDoce administrations were more effective than IV docetaxel in inhibiting the 
progression of renal cell carcinoma. The IT NanoDoce groups (female) showed almost no/no evidence of tumor on 
completion of study. NanOlogy also conducted Study Number D-PRe-05-2018, Evaluation of the Efficacy of 
Intratumoral NanoDoce against Primary and Secondary Renca Renal Cell Carcinoma in BALB/c Mice. The Renca 
model of mouse renal cell carcinoma was used to evaluate the efficacy of IT NanoDoce against primary and 
secondary tumors compared to untreated and vehicle-treated mice and mice treated with IV docetaxel. NanoDoce 


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administered IT and intratumoral/peritumoral at 30 mg/kg and 60 mg/kg achieved potential therapeutic activity, 
defined as tumor growth inhibition > 60%. With the exception of 60 mg/kg administered IT, all NanoDoce had 
significantly greater tumor growth inhibition compared to IV docetaxel (p < 0.01). 
To support development of NanoDoce for an indication of treatment of genitourinary neoplasms, seven nonclinical 
toxicology studies were conducted.  Two studies (non-GLP Study D-TR-03-2017 and GLP Study D-TR-04-2017) 
evaluated the effects of up to four weekly repeat-dose intravesical instillations of NanoDoce suspensions at 1.6 
mg/mL (3.2 mg/kg), 5 mg/mL (10 mg/kg), 15 mg/mL (30 mg/kg) or 40 mg/mL (80 mg/kg) into the urinary bladder of 
female rats. The maximum tolerated dose (MTD) and no-observed-adverse-effect-level (NOAEL) for four weekly 
NanoDoce intravesical instillations was determined to be 40 mg/mL, which is also the maximum feasible dose (MFD) 
based on NanoDoce solubility.  Two studies (non-GLP Study D-TRab-02-2017 and GLP Study D-TRab-03-2017) were 
conducted to evaluate the effects of a single direct intramural injection of NanoDoce into the urinary bladder wall in 
male and female rabbits. NanoDoce was administered at the following doses: 1.6 mg/mL (0.48 mg/kg), 5 mg/mL (1.5 
mg/kg), 15 mg/mL (4.5 mg/kg), or 40 mg/mL (12 mg/kg). The MTD was determined to be 40 mg/mL and a NOAEL was 
not determined. Non-GLP Study D-TR-02-2017 was conducted to evaluate the effects of intra-prostatic 
administration of NanoDoce. Male rats were administered a single dose of NanoDoce at 5 mg/mL (4 mg/kg), 10 
mg/mL (8 mg/kg), 20 mg/mL (16 mg/kg), or 40 mg/mL (32 mg/kg) as two 100 uL injections to each lobe of the 
prostate and the MTD was determined to be 40 mg/mL. Two studies (non-GLP Study D-TR-06-2018 and GLP Study D-
TR-07-2019) evaluated the effects of a single injection of NanoDoce into the kidney of male and female rats. 
NanoDoce suspensions were delivered as four distinct injections into the renal cortex at the following doses: 0.625 
mg/kg (0.5 mg/mL), 2.5 mg/kg (2.0 mg/mL), 12.5 mg/kg (10 mg/mL), 25 mg/kg (20 mg/mL), and 50 mg/kg (40 
mg/mL). Toxicity and toxicokinetic evaluations were performed for 8 (Study D-TR-06-2018) and 28 days (Study D-TR-
07-2019) after injection. The MTD at 8 days was determined to be 12.5 mg/kg and the NOAEL at 28 days was 
established to be 12.5 mg/kg with a corresponding AUC0-672 of 1,440 ng*hr/mL. 
Clinical Summary: 
NanoDoce has not been administered to humans in a clinical trial to date. An extensive series of clinical studies were 
conducted to assess the safety of docetaxel formulated as Taxotere. In addition, intravesical administration of 
docetaxel in patients with bladder cancer has demonstrated safety and tolerability (McKiernan 2006; Laudano 2010; 
Barlow 2009a, Barlow 2009b, Barlow 2013).  
NanOlogy provided NanoDoce drug product to an Investigator under Investigator-sponsored single patient expanded 
access. The patient was an 82-year-old man with recurrent, muscle-invasive urothelial carcinoma of the bladder. The 
subject was not a candidate for cystectomy and treatment with chemo-radiation resulted in continued bleeding.  
Under the individual patient expanded access IND, a direct injection procedure and three intravesical instillations 
with NanoDoce were administered. The subject died due to metastatic disease unrelated to the investigational 
product. 
Relevant Literature:  
Although docetaxel is not approved for the indication of urothelial carcinoma, it has been used off-label 
intravenously and intravesically for patients with bladder cancer.  
• 
Intravenous docetaxel is a widely accepted systemic treatment for advanced bladder cancer. Regulatory 
authorities worldwide have accepted docetaxel as a community standard and the National Comprehensive 
Cancer Network recommends docetaxel as second-line therapy for metastatic bladder cancer (Albany 2015).  


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• 
Intravesical administration of docetaxel in patients with BCG-unresponsive non-muscle invasive bladder 
cancer (NMIBC) has been reported. A Phase 1 trial investigated intravesical docetaxel in 18 subjects with 
recurrent high-grade Ta, T1 and Tis NMIBC for whom BCG had failed (McKiernan 2006). Barlow (2009) 
included the Phase 1 subjects in a retrospective analysis. Laudano (2010) followed-up by reporting long-
term results from the Phase 1 trial. Barlow (2013a) rolled the Phase 1 results and the retrospective review 
into a long-term analysis focused on survival outcomes, with an emphasis on maintenance treatment. 
Barlow (2009b) conducted a study to evaluate the durability of response for patients with BCG-unresponsive 
NMIBC treated with intravesical docetaxel in a combined induction and maintenance regimen. In general, 
these studies report low grade local bladder adverse events (AE) including Grade 1 dysuria, Grade 1 
hematuria, Grade 2 hematuria, Grade 1 frequency, and Grade 1 urgency. Systemic toxicity was not reported. 
Initial complete response (CR) rates in these studies ranged from 22% to 76.9% (with median follow-up 
ranging from 13 months to 48.3 months). 
Importance of the study: 
Bladder cancer is the sixth most common cancer in the United States, with an estimated 79,030 new cases and 
16,870 deaths from the disease predicted in 2017. Most patients (approximately 75%) with bladder cancer are 
diagnosed with disease confined to the mucosa or submucosa, classified as NMIBC (Babjuk 2015). NMIBC is further 
stratified as low, intermediate or high-risk. Most patients with high-risk NMIBC are treated with transurethral 
resection of the bladder tumor (TURBT) followed by intravesical chemotherapy. The three therapies currently 
approved by FDA for intravesical use, bacillus Calmette-Guérin (BCG), Valrubicin, and thiotepa, are imperfect. Many 
patients do not respond to treatment, do not achieve a lasting response, and/or encounter serious treatment-related 
toxicities (TICE BCG Package Insert 2009, Barlow 2013b, Babjuk 2017, Dinney 2013, Steinberg 2000, Hollister 1980). 
BCG is the current gold standard for intravesical therapy; however, 50% of patients treated with BCG experience 
recurrence (Barlow 2013). Patients experiencing BCG failure have a 50% chance of disease progression (Barlow 2013; 
McKiernan 2006; Babjuk 2015). Therefore, BCG failures represent the highest-risk subgroup of high-risk NMIBC. 
Approximately 25% of patients with bladder cancer present with a tumor invading the muscle layer of the bladder 
wall. Muscle invasive bladder cancer (MIBC) is associated with a high rate of recurrence and poor overall prognosis 
despite aggressive local and systemic therapies. For decades, radical cystectomy has been the mainstay of treatment 
for muscle invasive bladder cancer. Despite providing excellent local control, surgery alone does not result in optimal 
survival rates. Further, radical cystectomy is associated with considerable morbidity and mortality, as well as notable 
long-term complications and negative impacts on quality of life. There is increasing support for bladder sparing 
approaches to muscle invasive bladder cancer treatment for those who cannot or will not undergo radical 
cystectomy (Park 2014, Smith 2013, Mak 2014).  
2.2 
RATIONALE  
This Phase 1/2 study will include subjects with NMIBC and MIBC. It is hypothesized that the intravesical instillation of 
NanoDoce will establish a depot of drug within the bladder, providing sustained release of docetaxel within the 
bladder over time. Direct injection of NanoDoce to the tumor bed after TURBT may, in the short term, kill residual 
tumor cells missed by surgery and, in the long term, slowly release drug throughout the resection site over time to 
prevent recurrence.   


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2.3 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 KNOWN POTENTIAL RISKS  
There are no known potential risks from NanoDoce injection into the bladder wall of humans.  
Based on published studies of docetaxel, intravesical instillation toxicities include dysuria, hematuria, frequency, and 
urgency. Other adverse reactions are facial and body flushing/erythema, limb cramps, rash, UTI, exhaustion, pain, 
incontinence, nocturia, general flu-like symptoms, decreased appetite, lightheadedness and premature docetaxel 
void.   
The risks associated with intravenous docetaxel are described in the Taxotere Package Insert. The most common 
adverse reactions across all Taxotere indications are infections, neutropenia, anemia, febrile neutropenia, 
hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid 
retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence 
varies depending on the indication.  
2.3.2 KNOWN POTENTIAL BENEFITS  
There are no known potential benefits of direct bladder wall injection or intravesical administration of NanoDoce in 
humans.  
Published studies of docetaxel administered as an intravesical instillation to subjects with BCG-unresponsive NMIBC 
demonstrated an initial CR rate of between 22% and 76.9%, with median follow-up ranging from 13 months to 48.3 
months.  
3 
OBJECTIVES AND PURPOSE 
The primary objective of this study is to evaluate the safety and tolerability of NanoDoce injected directly into the 
bladder wall and instilled intravesically.  
Secondary objectives are (a) to characterize the pharmacokinetics (PK) of docetaxel when injected directly into the 
bladder wall in the presence of intravesical instillation; and (b) to determine whether any of the NanoDoce 
concentrations (0.75, 1.5, 2.5, or 3.75 mg/mL administered by injection; 2.0 or 3.0 mg/mL administered by 
intravesical instillation) show signs of preliminary efficacy.  
4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 DESCRIPTION OF THE STUDY DESIGN 
This open-label Phase 1/2 study will enroll subjects with pathological or cytological diagnosis of high-risk NMIBC or 
MIBC. Subjects will be stratified into two treatment groups, Group 1 (NMIBC) and Group 2 (MIBC). The study drug 
will be delivered by direct injection into the bladder wall and by intravesical instillation. At Visit 2, all subjects will 
receive NanoDoce injected into the index tumor resection site on the bladder wall, immediately following TURBT, 
followed by an initial NanoDoce intravesical instillation (within 2 hours of the direct injection).  


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Group 1 (NMIBC) and Group 2 (MIBC) Subset  
After a recovery period, Group 1 subjects will proceed to the 3-month Induction period. Subjects will be assessed for 
recovery (TURBT resection site healing) at Visit 4, at which point the Investigator will evaluate subject symptoms, 
pathology (if available), gross hematuria or urinalysis findings. If the Investigator determines that the subject has not 
recovered at Visit 4, evaluations will be repeated at least every 2 weeks until the subject has recovered and 
intravesical NanoDoce can be administered.   
The 3-month Induction period consists of 6 weekly NanoDoce intravesical instillations, followed by 6 weeks of rest. 
After the Induction period, subjects will proceed to a 3-month Maintenance period, consisting of 3 weekly NanoDoce 
intravesical instillations, followed by 9 weeks of rest. Subjects will return at Visit 13 for an End of Treatment study 
visit. Plasma samples will be collected at Visit 2 (prior to NanoDoce injection and at 1, 2, 6, and 24 hours post-
injection), at Visit 3, at Visit 4 (prior to NanoDoce intravesical instillation and at 1, 2, 6, and 24 hours post- intravesical 
instillation), at Visits 5-12 prior to the NanoDoce intravesical instillation, and at End of Treatment to characterize the 
PK of docetaxel. 
Subjects will be evaluated for tumor recurrence or disease progression with cystoscopy and urine cytology at Visit 10, 
and End of Treatment, and at any time at the discretion of the Investigator. Biopsy is to be performed at any time at 
the discretion of the Investigator for positive or suspicious cytology or cystoscopic findings. Any subject terminating 
early will be required to complete all End of Treatment assessments. An additional Safety visit will be required if the 
End of Treatment visit is not conducted 45 days after the last administration of NanoDoce. A PK plasma sample will 
be collected at the End of Treatment visit. Institution pathology data will be collected for any resection, cystectomy 
or biopsy specimen (to include, but not limited to bladder resection, cystectomy or node tissue) at any time during 
the study or early withdrawal. 
 
Progression, PFS and post-study bladder treatment or concomitant therapy will be collected at  9 and 12 months 
following the Day 1 NanoDoce injection, for subjects who have retained their bladders (non-cystectomy subjects). 
Group 2 (MIBC) 
At the end of Visit 3, Group 2 (MIBC) subjects may proceed to institutional standard of care (SOC) treatments and 
return for the End of Treatment study visit 45 days (+/- 5 days) after Visit 2. Alternately, at Visit 3, a subset of 
subjects, as determined by the treating Investigator, who are deemed ineligible for cystectomy and intolerant to 
existing standard of care chemotherapy or other treatment, may be offered the option to receive Induction and 
Maintenance intravesical NanoDoce (according to the regimen described for Group 1) (referred to hereafter as the 
“Group 2 Subset”). The Investigator must determine and document there are no existing or available, standard of 
care treatment options for the subject. Only at that time, will the Induction and Maintenance treatment be offered 
to the subject for consideration.    
Plasma samples will be collected at Visit 2 (prior to NanoDoce injection, at 1, 2, 6, and 24 hours post-injection), Visit 3 
and at the End of Treatment visit to characterize the PK of docetaxel.  
 
Progression, PFS and post-study bladder treatment concomitant therapy will be collected at 6, 9 and 12 months 
following the Day 1 NanoDoce injection, for subjects who have retained their bladders (non-cystectomy subjects).  
Subjects who proceed to cystectomy will no longer have data collected after that point. 


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Dose Escalation: Groups 1 and 2 
The study will consist of a dose escalation phase and a dose confirmation phase for the direct injection of NanoDoce 
concentrations (0.75, 1.5, 2.5, or 3.75 mg/mL) for Groups 1 and 2; dose escalation will also occur for the intravesical 
instillation of NanoDoce concentrations (2.0 and 3.0 mg/mL) for Groups 1 and 2. See Section 6.1.7 Starting Dose and 
Dose Escalation for details. 
 
4.2 
ENDPOINTS 
 
4.2.1 PRIMARY ENDPOINT 
The primary endpoint will be safety and tolerability as demonstrated by AE, changes in laboratory assessments, 
physical examination findings and vital signs. 
4.2.2 SECONDARY ENDPOINTS 
The secondary endpoints will be: 
• 
Concentration of docetaxel in the systemic circulation post-injection in the presence of intravesical 
instillation (as determined by PK analysis); 
• 
PFS defined as tumor recurrence or disease progression at Visit 10 and Visit 13;  
• 
OS determined by survival time following NanoDoce injection. 
 
4.2.3 EXPLORATORY ENDPOINTS 
The exploratory endpoints will be to determine whether exposure to NanoDoce will affect: 
• 
Tumor-specific antigens (IHC); 
• 
Immunophenotyping of T cells, B cells and monocytes. 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
PARTICIPANT INCLUSION CRITERIA 
Patients who meet the following criteria will be considered eligible for participation in the study: 
• 
Signed informed consent; 
• 
Age ≥18 years; 
• 
Patients with pathological or cytological diagnosis of: 
o 
High risk NMIBC1; 
 
High grade (HG) T1; 
 
Any recurrent, HG Ta; 
 
HG Ta, >3 cm (or multifocal); 
 
Any carcinoma in situ (CIS); 
 
Any BCG failure2 in HG patient; 
 
Any variant histology; 
 
Any lymphovascular invasion (LVI), to include any HG prostatic urethral involvement; 
o 
MIBC; 


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• 
Urothelial carcinoma confirmed by biopsy, urine cytology, computed tomography scan (CT) or other 
institution-approved diagnostic methodology; 
• 
All visible tumors removed during TURBT (as is reasonable, ensuring patient safety); 
• 
Performance Status (ECOG) 0-2 at study entry; 
• 
Life expectancy of at least 6 months; 
• 
Adequate marrow, liver, and renal function; 
o 
ANC ≥ 1.5 x 109/L; 
o 
Hemoglobin ≥ 9.5 grams/dL; 
o 
Platelets ≥ 75 x 109/L; 
o 
Total bilirubin ≤ 1.5x institutional ULN; 
o 
AST/ ALT ≤ 2.5x institutional ULN; 
o 
Creatinine ≤ 1.5x institutional ULN; 
• 
Adequate method of birth control. 
 
1. As defined in the AUA/SUO Guideline (Chang 2016) 
2. BCG failure to be determined using the definition of BCG-unresponsive NMIBC as in “BCG-Unresponsive Nonmuscle Invasive 
Bladder Cancer: Developing Drugs and Treatment Guidance for Industry.” 
 
a. BCG-unresponsive disease is defined as being at least one of the following: 
 
i. Persistent or recurrent CIS alone or with recurrent Ta/T1 (noninvasive papillary disease/tumor invades the 
subepithelial connective tissue) disease within 12 months of completion of adequate BCG therapy 
 
 
ii. Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy 
 
 
iii. T1 high-grade disease at the first evaluation following an induction BCG course. 
 
b. In this context, adequate BCG therapy is defined as at least one of the following: 
i. At least five of six doses of an initial induction course plus at least two of three doses of maintenance 
therapy; 
 
 
ii. At least five of six doses of an initial induction course plus at least two of six doses of a second induction 
course.  
 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
Patients who meet the following criteria will be considered ineligible for participation in the study: 
• 
Metastatic disease; 
• 
Previous (within 12 months) or concurrent history of non-bladder malignancy, except for non-melanoma 
skin cancer; 
• 
Intravesical therapy within 4 weeks prior to consent (chemotherapy or immunotherapy including BCG 
administered directly into the bladder); 
• 
Resection surface area greater than 8 cm2; 
• 
Upper tract and urethral disease within 18 months; 
• 
Known hypersensitivity to any of the study drug components or reconstitution components; 
• 
Pregnant or breastfeeding; 
• 
Participation in the treatment phase of another clinical trial within 3 months prior to consent; 
• 
Investigator’s opinion of subject’s probable noncompliance or inability to understand the trial and/or give 
adequate informed consent; 
• 
Ongoing drug or alcohol abuse. 
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Subjects will be recruited at 5 study sites.  
It is not anticipated that any advertising will be required for recruiting to the study.  


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5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Subjects are free to withdraw from participation in the study at any time upon request.  
At any time during the study, if there is tumor recurrence or disease progression, decision to remove from study will 
be a consensus between the Investigator, Medical Monitor and Study Director.  
The reason for withdrawal will be documented in the source notes and in the Electronic Data Capture system (EDC).  
Any potential or confirmed-related event, (clinical AE, laboratory abnormality, or other medical condition/situation) 
occurring, and/or DSMB determination which may be attributed to the withdrawal, must be documented and 
followed for the safety of the subject.  
Should the Investigator feel it to be in the best interest of the subject to be withdrawn from the study, the 
Investigator will immediately contact the Medical Monitor to discuss the reasons for withdrawal. 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
The Sponsor should be notified immediately when a subject is removed or withdrawn from the study after any 
treatment with study drug, as every attempt should be made to capture as much information following treatment as 
possible.  
When a subject is terminated after the first study drug dose, all efforts will be made to ensure the End of Treatment 
procedures are performed.      
Subjects that refuse or fail to appear for clinic visits following Visit 2 and fail to respond to or cooperate with 
reasonable and diligent attempts at contact, will be discontinued from the study and be considered lost-to-follow-up. 
Reasonable and diligent attempts such as dates and content of phone calls, emails and registered mail should be 
recorded in the subject’s record. 
If a Group 1 subject repeatedly misses study visits or is non-compliant following Visit 2, and where the majority of 
data is not collected or most of follow-up induction or maintenance visits are not completed, Sponsor may exercise 
the option to replace that subject in the cohort.  All data reported and collected will be included in the assessment of 
safety. 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
This study may be temporarily suspended or prematurely terminated, if there is sufficient reasonable cause. Written 
notification, documenting the reason for the study suspension or termination, will be provided by the suspending or 
terminating party. If the study is prematurely terminated or suspended, the Investigator(s) will promptly inform the 
IRB(s) and will provide the reasons for the termination or suspension. 
Circumstances that may warrant termination include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to subjects; 


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o 
Routine Medical Monitoring determining a requirement for an ad hoc meeting of the DSMB, and/or 
routine DSMB reviews, will allow for termination of study based on unacceptable risk, which will 
consider all safety evaluations and DLTs.   
o 
Groups 1, 2 and Group 2 subset will be considered independently for purposes of termination.  
o 
In the direct injection dose escalation phase, the study may be terminated for a group, at the 
lowest dose, if at least two of six subjects in that group experience DLT (as defined in Section 6.1.7).  
o 
In the intravesical instillation dose escalation phase, the study may be terminated for a group if, at 
the lowest dose, at least two of three or two of six subjects in that group experience DLT (as 
defined in Section 6.1.7).  
• 
Insufficient compliance with protocol requirements; 
• 
Data that are not sufficiently complete and/or evaluable; 
• 
Determination of futility. 
The study may resume once concerns about safety, protocol compliance, and data quality are addressed and satisfy 
the Sponsor, IRB, and/or FDA. 
6 
STUDY DRUG 
 
6.1 
STUDY DRUG(S) AND CONTROL DESCRIPTION 
 
6.1.1 ACQUISITION 
NanoDoce is manufactured by CritiTech, Inc. (Lawrence, KS) and provided for use in this study. Study drug will not be 
shipped to the study site until all regulatory documentation has been provided to Sponsor by the site and the site is 
ready for study initiation, at which time the study drug will be released by US Biotest for shipment. Shipment will be 
via courier, temperature controlled at 59˚ to 86˚F (15˚ to 30˚C) just prior to the site initiation visit. Study drug will be 
shipped to the institution pharmacy where it will be stored according to the conditions required (see Section 6.1.3). 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
The NanoDoce Suspension kits (Clinical Supplies Kit) provided to the study sites will contain study drug for all 
treatments and dosage groups in the study.  
Each ‘Clinical Supplies Kit for NanoDoce Clinical Trials’ contains one vial of NanoDoce and one vial of Sterile 
Reconstitution Solution (1% Polysorbate 80 and 8% Ethanol in 0.9% Sodium Chloride for Injection, USP). The 
NanoDoce 60 mL vial contains sterile nanoparticulate docetaxel (100 mg/vial), appearing as a white powder. When 
ready for use, the powder is suspended using the Sterile Reconstitution Solution provided in the kit.  


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The Clinical Supplies Kit will be labeled as: 
 
The NanoDoce vial will be labeled as:  
 
 
The reconstitution solution vial will be labelled as: 
 
6.1.3 PRODUCT STORAGE AND STABILITY 
 
Clinical Supplies Kits containing NanoDoce 100 mg powder vials and sterile reconstitution solution must be stored at 
the institution pharmacy, under limited access conditions and temperature controlled at 59˚ to 86˚F (15˚ to 30˚C). 
Clinical Supplies Kit for NanoDoce Clinical Trials 
Each kit contains: 
• 
1 vial of NanoDoce (sterile nanoparticulate docetaxel)  
Powder for Suspension, 100 mg per vial                                                                                     
 
 
• 
1 vial of Sterile Reconstitution Solution for  
NanoDoce Powder for Suspension, 5 mL per vial 
Caution: New Drug – Limited by federal law to investigational use – 
                                                              For single use only                                                                       ##### 
NanoDoce (sterile nanoparticulate docetaxel) Powder for Suspension, 100 mg vial 
Lot.: ________ 
Prior to reconstitution, Store at 59° to 86°F (15° to 30°C). 
Reconstitute according to the Instruction Sheet and the procedure in the clinical protocol. 
After reconstitution, store the suspension per Instruction Sheet. 
Caution: New Drug – Limited by federal law to investigational use 
For single use only 
Manufactured by: CritiTech, Inc., 1849 East 1450 Road, Lawrence, KS 66044 
Manufactured for: US Biotest, Inc., 231 Bonetti Drive, Suite 240, San Luis Obispo, CA 93401      XXXXX 
Sterile Reconstitution Solution for NanoDoce (sterile nanoparticulate docetaxel) Powder for 
Suspension 
Lot No.: ________ 
Contains: 5 mL of 1% Polysorbate 80 (NF) and 8% Ethanol (USP) in 0.9% Sodium Chloride for Injection 
(USP) per vial 
Prior to use, store at 59° to 86°F (15° to 30°C). 
For single use only  
Caution: New Drug – Limited by federal law to investigational use 
Manufactured by: The University of Iowa Pharmaceuticals, 115 S Grand Ave.,  
                                  Iowa City, IA 52242 
Manufactured for: US Biotest, Inc., 231 Bonetti Drive, Suite 240,  
                                  San Luis Obispo, CA 93401                                                                                    XXXXXX 


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Reconstitution will be performed in the pharmacy. Once the NanoDoce has been reconstituted, it will be delivered 
for injection or instillation at the desired location (treatment area, clinic or operating room). If the reconstituted drug 
is not delivered immediately, the syringe may be stored according to pharmacy manual instructions until delivery. 
Each vial and each syringe must be labelled according to institution requirements as well with the subject study 
number. 
6.1.4 PREPARATION 
A prescription (drug order) will be provided to the pharmacy for each subject detailing the subject study number, the 
assigned cohort dose, and the date and time required for administration, as well as any institution-required 
instructions for study drug identification. The drug order should be provided to the Pharmacy at least 24 hours prior 
to administration time, or per institution requirements. The site will provide 0.9% Sodium Chloride for Injection, USP, 
a sterile syringe with a sterile 18-gauge needle (or larger bore) for sterile injectable drug preparation and a suitable 
sterile container to prepare secondary dilutions, as necessary.   
Direct Injection: Once the drug has been reconstituted to the required cohort-assigned dose for injection (3.0, 6.0, 
10.0 or 15.0 mg), the maximum injection volume of 4.0 mL will be withdrawn from the vial into a syringe. 
Intravesical Instillation: Once the drug has been reconstituted to 2.0 mg/mL or 3.0 mg/mL, the appropriate volume of 
the NanoDoce suspension will be withdrawn from the vial and transferred to an appropriate delivery receptacle for 
instillation. 
Each Clinical Supplies Kit, including entire contents, is for a single-subject use only. Reconstitution will be performed 
by study-delegated pharmacy staff and the final study drug concentration (whether for direct injection or intravesical 
instillation) will be delivered by the pharmacy to the Investigator, or designee. Sponsor will provide separate written 
instructions in the pharmacy manual and an instructional video will be provided by CritiTech to each site at the 
Initiation Visit for training.  
NanoDoce must be administered no more than 4 hours after the initial reconstitution. 
6.1.5 DOSING AND ADMINISTRATION 
Groups 1 and 2: Direct Injection  
NanoDoce will not be injected if there is any evidence of bladder perforation (visible fat or bowel). Confirmed or 
suspected perforation prior to NanoDoce injection will terminate participation in the study and the subject will be 
considered a Screen Fail. If perforation is not detected during the resection and the subject proceeds to NanoDoce 
injection and/or instillation, the subject will terminate participation in the study at the time the perforation is 
detected and proceed to the End of Treatment and safety visit, 45 days after the last study drug dose. The sponsor 
may replace that subject in the cohort.  
Subjects will receive the assigned NanoDoce injection dose into the base of the index tumor resection site on Visit 2 
immediately post-TURBT. The index tumor resection site is defined as the largest resection site (should not exceed 
8.0 cm2) if multiple resections are performed. If multiple resections are performed, only the index tumor resection 
site will receive NanoDoce injections.  
Adjustable tip-length cystoscopy needles are to be used for injection into the resected bladder wall. The needle tip to 
be adjusted to 2 mm (per manufacturer recommendation) for injections in the dome area of the bladder and 3 – 4 
mm for injections in the side area of the bladder. A total volume of 4.0 mL of NanoDoce will be injected in 0.5 mL 


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increments, approximately 1 cm apart, with up to 8 injections into the index tumor resection site. Injections will be 
performed in a tangential approach (grid-like pattern to cover the resection site) so the needle tip is viewable under 
direct visualization by cystoscope. The investigator will inject up to 5 mm outside of the resection margin.  
The total dose administered will not exceed the assigned cohort dose of 3.0 (0.75 mg/mL), 6.0 (1.5 mg/mL), 10.0 (2.5 
mg/mL), or 15.0 (3.75 mg/mL) mg. 
Groups 1 and 2: Visit 2 Intravesical Instillation  
The initial intravesical instillation will immediately follow the NanoDoce direct injection (<2 hours). NanoDoce will be 
instilled intravesically in the bladder for a maximum of 30 minutes (+/- 5 min).   
The total dose administered will not exceed the assigned cohort dose 50 mg in 25 mL of saline for a final 
concentration of 2.0 mg/mL or 75 mg in 25 mL of saline for a final concentration of 3.0 mg/mL.     
The subject will be in supine position. Local anesthetic gel is allowed for catheter placement. The urinary catheter 
will be inserted into the bladder using sterile technique. Isotonic saline or sterile water is the only distending medium 
which will be allowed in this study. Following intravesical instillation, the subject will be asked to change position 
every 15 minutes to ensure uniform coating of study medication to the bladder wall. On Visit 2, at the end of the 30-
minute dwell time, the instillate will be drained by catheter into an appropriate receptacle; the catheter will be 
removed, and the drained fluid and catheter will be disposed of, per institution requirements.  
Group 1 and Group 2 Subset: Induction and Maintenance Intravesical Instillation  
If Induction and Maintenance intravesical instillations are administered in a hospital setting, the instillate will be 
drained by catheter into an appropriate receptacle; the catheter will be removed, and the drained fluid and catheter 
will be disposed of, per institution requirement. If the subject is not catheterized, the subject will void in the toilet. 
Total instillate retention time will be recorded for study purposes. 
Visits 4-9 Induction:  NanoDoce will be instilled in the bladder once/week for 6 weeks for a maximum of 120 minutes 
(+/- 10 min).  
Visits 10-12 Maintenance:  NanoDoce will be instilled in the bladder once/week for 3 weeks for a maximum of 120 
minutes (+/- 10 min).  
 
6.1.6 ROUTE OF ADMINISTRATION 
NanoDoce will be administered by two routes: as a direct injection to the bladder wall and as intravesical 
instillation(s) in the bladder. 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
Direct Injection 
The study will consist of a dose escalation phase and a dose confirmation phase for the direct injection of NanoDoce 
concentrations (0.75, 1.5, 2.5, or 3.75 mg/mL) for Groups 1 and 2.  


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Table 1: NanoDoce Direct Injection Dose-Escalation 
Cohort 
NanoDoce Suspension  
Concentration 
Maximum # of 
Injections 
Total NanoDoce Administered  
‘Not to Exceed’  
1 
0.75 mg/mL 
8 
3.0 mg  
2 
1.5 mg/mL 
8 
6.0 mg 
3 
2.5 mg/mL 
8 
10.0 mg 
4 
3.75 mg/mL 
8 
15.0 mg 
 
During direct injection dose escalation, cohorts will be enrolled sequentially starting at the lowest concentration 
(0.75 mg/mL) (Table 1). Cohorts will enroll separately for Groups 1 and 2. Each cohort will have a planned minimum 
of three subjects for Group 1 and three subjects for Group 2. Escalation to the next cohort for Group 2 will proceed 
following review of Group 1 data by the DSMB. All clinical data from subjects in each cohort, including all DLTs 
described in this section and excluding PK, will be reviewed and evaluated by the Medical Monitor and DSMB (based 
on the DSMB charter) on an ongoing basis, in addition to at Visits 4, 6 and 9, to determine if the dose received is 
considered safe and tolerable, and to determine if dose escalation may occur.   
If the DSMB determines cohort 1 (0.75 mg/mL) is safe (no DLT), escalation to the next dose level, cohort 2 (1.5 
mg/mL), will occur. If >2 DLT occurs in the first three subjects, the study will stop. If 1 DLT occurs at cohort 1, three 
additional subjects will be added to cohort 1. If >1 DLT occurs in the additional three subjects, the study will stop. If 
no additional DLT occurs in the additional three subjects, the study will escalate to the next dose level, cohort 2 (1.5 
mg/mL).  
Three subjects will be dosed at cohort 2 (1.5 mg/mL). If the DSMB determines cohort 2 is safe (no DLT), escalation to 
the next dose level, cohort 3 (2.5 mg/mL), will occur. If >2 DLT occurs in the first three cohort 2 subjects, the study 
will return to the previous (lower) dose, cohort 1 (0.75 mg/mL), and proceed to dose confirmation. If 1 DLT occurs at 
cohort 2, three additional subjects will be added to cohort 2. If > 1 DLT occurs in the three additional cohort 2 
subjects, the study will return to the previous (lower) dose, cohort 1 (0.75 mg/mL), and proceed to dose 
confirmation. If no additional DLT occurs in the additional three subjects, the study will escalate to the next dose 
level, cohort 3 (2.5 mg/mL).  
Three subjects will be dosed at cohort 3 (2.5 mg/mL). If the DSMB determines cohort 3 is safe (no DLT), escalation to 
the next dose level, cohort 4 (3.75 mg/mL), will occur. If > 2 DLT occurs in the first three cohort 3 subjects, the study 
will return to the previous (lower) dose, cohort 2 (1.5 mg/mL), and proceed to dose confirmation. If 1 DLT occurs at 
cohort 3, three additional subjects will be added to cohort 3. If > 1 DLT occurs in the three additional cohort 3 
subjects, the study will return to the previous (lower) dose, cohort 2 (1.5 mg/mL), and proceed to dose confirmation. 
If no additional DLT occurs in the additional three subjects, the study will escalate to the next dose level, cohort 4 
(3.75 mg/mL).  
Three subjects will be dosed at cohort 4 (3.75 mg/mL). If the DSMB determines cohort 4 is safe (no DLT), dose 
confirmation at cohort 4 (3.75 mg/mL) will occur. If > 2 DLT occurs in the first three cohort 4 subjects, the study will 
return to the previous (lower) dose, cohort 3 (2.5 mg/mL), and proceed to dose confirmation. If 1 DLT occurs at 
cohort 4, three additional subjects will be added to cohort 4. If > 1 DLT occurs in the three additional cohort 4 
subjects, the study will return to the previous (lower) dose, cohort 3 (2.5 mg/mL), and proceed to dose confirmation. 
If no additional DLT occurs in the additional three subjects, the study will complete enrollment at cohort 4 (3.75 
mg/mL) in dose confirmation.  


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The dose most suitable for further evaluation will be the highest dose with an acceptable safety and tolerability 
profile as determined by the DSMB. If one or fewer subjects in a six-subject cohort, or no subjects in a three-subject 
cohort at the highest dose, experience DLT, that cohort will be taken into the dose confirmation phase. If greater 
than one subject in a six-subject cohort experience DLT, the previous dose will be taken into the dose confirmation 
phase.   
Once the dose deemed appropriate for further evaluation has been determined by the DSMB, additional subjects will 
be enrolled to provide up to a total of up to 9 subjects dosed at that dose level. 
Intravesical Instillation 
The study will also dose escalate Groups 1 and 2 for the intravesical instillation of NanoDoce concentrations (2.0 and 
3.0 mg/mL). In the intravesical instillation dose escalation phase, all subjects in Group 1 will be enrolled at the lowest 
concentration of 2.0 mg/mL for the Visit 2 instillation. If the dose is well-tolerated, Group 1 subjects will continue to 
receive 2.0 mg/mL through Visit 6, then escalate to 3.0 mg/mL intravesical instillations for the subsequent Induction 
and Maintenance intravesical instillations following ongoing data review by the Medical Monitor and the DSMB.  
Group 2 subjects will be enrolled at the lowest concentration of 2.0 mg/mL for the Visit 2 instillation for all direct 
injection doses. If the dose is well-tolerated for the Group 1 subjects (following ongoing data review by the Medical 
Monitor and the DSMB) Group 2 and Group 2 subset subjects will escalate to 3.0 mg/mL intravesical instillations for 
the dose confirmation phase of the study.  
Escalation to 3.0 mg/mL in each group will proceed, independent of the other group. If no subjects in cohort 1 at 2.0 
mg/mL experience a DLT, the intravesical dose will escalate to 3.0 mg/mL for that group as described below. If two or 
more subjects in cohort 1 experience a DLT at 2.0 mg/mL, then the study will stop. If one of the three subjects in 
cohort 1 experiences a DLT at 2.0 mg/mL, then an additional three subjects will be enrolled to cohort 1 at 2.0 mg/mL. 
If, in the additional three subjects at 2.0 mg/mL, no subjects experience a DLT, then the dose will remain at 2.0 
mg/mL as described below. If >1 DLT occurs in the additional three subjects, the study will stop. 
Definition of DLT 
Included in the DSMB’s review of AEs and general study data pertaining to safety (laboratory results, vital signs, 
physical examination findings) there will be rules for non-escalation. Any AE that is considered related or probably 
related to NanoDoce is potentially a DLT. The definition of a DLT will be determined by the DSMB and the Sponsor for 
AEs. DLTs will, in addition, include the following: 
• 
Procedure-related events that require hospitalization or surgical intervention and some procedure-related 
events that require medical intervention; 
• 
All Grade 3-4 AE which are possibly related to study drug will be considered DLT except: 
o 
Grade 3 nausea or Grade 3-4 vomiting and diarrhea that persist for less than 48 hours in patients 
who have not received optimal anti-emetic or anti-diarrhea prophylaxis; 
o 
Grade 3 fatigue less than 5 days; 
o 
Grade 3 laboratory abnormalities that are not clinically significant and return to normal (with or 
without intervention) within 48 hours; 
• 
Grade 3 thrombocytopenia with clinically significant hemorrhage; 
• 
Grade 2 toxicity that prevents further treatment or persists for at least 3 weeks;  
• 
Any life-threatening event (unless there is a clear alternative explanation that the event is not related to the 
procedure or the investigational product itself). 
 


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6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
Group 1 and Group 2 Subset 
At any time during Induction or Maintenance, intravesical instillations will be withheld in weekly increments in the 
event of Grade 2 thrombocytopenia, anemia, neutropenia, hematuria (visible gross hematuria) or laboratory-
confirmed urinary tract infections until the infection is resolved. The hematuria and abnormal CBC values must 
resolve to a maximum of Grade 1.  
Group 2 
The study will evaluate one single NanoDoce intravesical instillation in each subject; therefore, there will be no dose 
adjustment or modification.                                                                                                                                                                          
6.1.9 DURATION OF THERAPY 
At Visit 2, NanoDoce will be injected directly into the index tumor resection site followed by a single intravesical 
instillation.  
Group 1 and Group 2 Subset 
Up to six Induction NanoDoce intravesical instillations and up to three Maintenance NanoDoce intravesical 
instillations will be administered. It is estimated that individual subject participation could last up to 33 weeks. 
Survival data will be collected up to 12 months; clinic visits will not be required. 
Group 2 
It is estimated that individual subject participation could last up to 64 days. Survival data will be collected up to 12 
months; clinic visits will not be required. 
6.1.10 TRACKING OF DOSE 
Not applicable. 
6.1.11 DEVICE SPECIFIC CONSIDERATIONS 
Not applicable. 
6.2 
STUDY DRUG ACCOUNTABILITY PROCEDURES 
The Investigator will maintain adequate records showing the receipt, dispensing, return, or other disposition of the 
investigational drug, including the date, quantity, lot number, and identification of subjects (number, initials as 
allowed) receiving study medication.  
Accountability will be conducted by the Pharmacy including details on the Clinical Supplies Kits, the individual 
NanoDoce vials, and the sterile reconstitution solution.  No used vials will be kept for accountability purposes, they 
will be disposed of according to the institution destruction procedures.  


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If Investigator determines that the full volume of NanoDoce cannot be administered, the Investigator will document 
the amount of NanoDoce injected or instilled and the volume remaining in the vial, in the source document and in 
the EDC. 
Under no circumstances will the Investigator supply clinical material to other Investigators or clinicians or allow the 
supplies to be used other than as directed by this protocol without the consent of the Sponsor.  
7 
STUDY PROCEDURES AND SCHEDULE 
 
7.1 
STUDY PROCEDURES/EVALUATIONS 
 
 
7.1.1 STUDY SPECIFIC PROCEDURES  
The following procedures and evaluations will be done as part of this study. 
• 
Complete medical history and demographics collection and documentation; 
• 
Concomitant prescription and non-prescription medication collection and documentation; 
• 
Urothelial carcinoma diagnosis and treatment documentation; 
• 
Comprehensive physical examination, including ECOG; vital signs, body weight and height; 
o 
Respiratory rate may not be measured at all institutions as SOC; this will not be a deviation. For 
those institutions providing the measurement, the data will be collected as described in Section 
7.3.  
• 
12-lead ECG; 
• 
PK sampling; 
• 
Routine clinical laboratory sampling; 
• 
Diagnostic biopsy and/or imaging with CT scans including, but not limited to histological reports to include 
lymph node data. A copy of the pathology report confirming the diagnosis must be filed in the subject’s 
study record;  
• 
Bladder tissue slides for immunohistochemistry staining collected during the course of the trial;  
• 
NanoDoce injection of the index tumor resection site post-TURBT; 
• 
Intravesical NanoDoce instillation(s); 
• 
Subject diary completion. 
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
Group 1 and Group 2 Subset 
At any point after the first administration of study drug, the care of the subject will be as dictated by the protocol but 
will allow for any other standard care routinely provided (such as pain relief, additional clinic visits, etc.).  
Group 2 
After the Visit 3 NanoDoce direct injection and intravesical instillation, subjects may proceed to SOC.  


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7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
Clinical laboratory assessments will be conducted at the local CLIA certified laboratory routinely used by the 
Investigator. 
Laboratory Assessments include: 
• 
Biochemistry analysis to be performed at Visits 1, 4, 10 and End of Treatment for Group 1 and Visits 1 and 
End of Treatment for Group 2 to include: Sodium, potassium, chloride, carbon dioxide (CO2), calcium, 
phosphorus, glucose, blood urea nitrogen (BUN), creatinine, serum lipase, serum amylase, alkaline 
phosphatase (ALP), total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate 
dehydrogenase (LDH), total protein, albumin, triglycerides, cholesterol, uric acid and calculated creatinine 
clearance;  
• 
Complete blood count (CBC) at each visit (except Visit 3 for Group 1 subjects) to include: Red blood cells 
(RBC), white blood cells (WBC) including complete differential, hemoglobin (Hgb), hematocrit (Hct), mean 
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), platelet (Plt) and reticulocyte count; 
• 
Urinalysis at each visit (except Visit 3 for Group 1 subjects) including specific gravity, hydrogen ion 
concentration (pH), RBC, WBC, protein, and glucose; 
• 
Activated partial thromboplastin time (aPTT) and prothrombin time (PT) to be performed at Visits 1, 4, 10 
and End of Treatment for Group 1 and Group 2 subset and at Visits 1 and End of Treatment for Group 2; 
• 
Fibrinogen assay to be performed at Visits 1, 4, 10 and End of Treatment for Group 1 and Group 2 subset 
and at Visits 1 and End of Treatment for Group 2.  
Blood for routine laboratory assessments will be collected and processed per institution requirements and 
guidelines.  
7.2.2 OTHER ASSAYS OR PROCEDURES  
7.2.2.1 PATHOLOGY EVALUATIONS 
Any tissue sample collected during the study will be processed per institution pathology standards, to include but not 
limited to: pathologist review of tissue blocks and histological quality check; pathologist clinical data review, 
including stage confirmation; and H&E staining.  
Additionally, once study eligibility is confirmed at Visit 2 (see Section 7.3.2), biopsy samples collected during the 
study (starting with initial TURBT) will be mounted on slides and shipped to a central laboratory for 
immunohistochemistry (IHC) research. Shipment process for the IHC slides to NeoGenomics will be described in the 
IHC Laboratory manual. 
7.2.2.2 PHARMACOKINETICS 
Plasma samples will be collected to characterize the PK of docetaxel. Visit 2 (Day 1) PK samples will be collected as of 
‘stop time’ of the last injection; Visit 4 (Day 1) PK samples will be collected as of ‘stop time’ of instillation. 


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Group 1 and Group 2 subset 
Plasma samples will be collected at Visit 2 (prior to NanoDoce injection and at 1, 2, 6, and 24 hours post-injection), at 
Visit 3, at Visit 4 (prior to NanoDoce intravesical instillation and at 1, 2, 6, and 24 hours post- intravesical instillation), 
at Visits 5-12 prior to NanoDoce intravesical instillation, and at the End of Treatment visit. Allowable visit 2 and visit 4 
windows will be: 10-minutes for hours 1 and 2, 20-minutes at 6 hours post and 30-minutes at 24 hours post.   
Group 2 
Plasma samples will be collected at Visit 2 (prior to NanoDoce injection and at 1, 2, 6, and 24 hours post-injection), 
Visit 3, and at the End of Treatment visit. Allowable Visit 2 windows will be: 10-minutes for hours 1 and 2,  20-
minutes at 6 hours post and 30-minutes at 24 hours post.  
7.2.2.2.1 
PK SPECIMEN PREPARATION, HANDLING, AND STORAGE 
PK samples will be drawn at the specified time for each visit, processed and stored frozen on-site until instructed to 
ship by the sponsor, at which time they will be batch-shipped to Covance Laboratories (Madison, WI) for analysis of 
docetaxel. Procedures for storage processing will be described in the PK Laboratory Manual provided at study 
initiation. 
7.2.2.2.2 
PK SPECIMEN SHIPMENT 
Shipment process for the PK samples to Covance Laboratories will be described in the PK Laboratory manual 
provided at study initiation. 
7.3 
STUDY SCHEDULE 
 
7.3.1 SCREENING (VISIT 1) 
Groups 1 and 2 will complete the Screening visit (Visit 1). Assessments, visits, and other assays performed prior to 
consent to the study for NanoDoce injection, will be performed according to the institution SOC and are not 
considered part of this study. The following procedures and assessments must be completed, documented and 
reviewed by the Investigator during the screening period, within 30 days prior to NanoDoce Visit 2 injection, unless 
otherwise indicated: 
• Written informed consent including comprehensive discussion of the study schedule, procedures and 
subject protocol requirements; 
• Complete medical history, including review of previous medical records and demographics; 
• Review and documentation of urothelial carcinoma diagnosis (diagnostic biopsy and/or imaging, 
cystoscopy and or cytology) obtained within three months of consent. A copy of the pathology report 
confirming the diagnosis must be filed in the subject’s study record;  
• Review and documentation of previous treatments including surgical, chemotherapy and immunologic 
records;  
• Review and documentation of all concomitant prescription and non-prescription medications; 
• Comprehensive physical examination within the 14 days prior to Visit 2; 
• ECOG Performance Status (Appendix A) within the 14 days prior to Visit 2; 


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• 12-lead ECG; 
• Vital signs (blood pressure, heart rate, respiratory rate and temperature) within the 14 days prior to Visit 
2; 
• Body weight and height; 
• Pregnancy test (urine) for females of child-bearing potential; 
• Sample collection and processing for clinical laboratory assessments (see Section 7.2.1) 
 
7.3.2 TRANS URETHRAL RESECTION OF BLADDER TUMOR (VISIT 2) 
Groups 1 and 2 will complete Visit 2. 
• Medical history confirmation (AE occurring prior to NanoDoce injection will be considered history); 
• Comprehensive physical examination (if not completed within the 14 days prior to Visit 2); 
• ECOG Performance Status assessment (if not completed within the 14 days prior to Visit 2);  
• Final review of inclusion and exclusion criteria and determination of eligibility prior to NanoDoce 
injection; 
• TURBT; 
o 
Confirmation of non-bladder perforation during TURBT must be documented and filed in the 
subject’s study record;  
o 
Trans-urethral resection surface area to be recorded (< 8 cm2); 
o 
If subject does not qualify or bladder perforation is confirmed, subject will not proceed to 
NanoDoce injection and will be considered a Screen Fail; 
• If continuation to NanoDoce injection is confirmed, the bladder resection tissue sample collected will be 
processed according to Section 7.2.2.1; 
 
7.3.3 NANODOCE TREATMENT - INJECTION & INTRAVESICAL INSTILLATION (VISIT 2 
CONTINUED) 
Groups 1 and 2 will complete Visit 2. 
• Baseline PK sample will be drawn prior to NanoDoce injection; 
o 
May be collected at any time during screening prior to TURBT procedure; 
• Vital signs (blood pressure, heart rate, respiratory rate) will be monitored and collected prior to 
NanoDoce injection; 
o 
Vital signs will be monitored and collected per SOC; it is expected during surgery and recovery, 
continuous vitals monitoring will be conducted; 
• NanoDoce injection of the resected bladder tumor;  
o 
Start time of first injection and stop time of last injection will be recorded; 
• Vital signs (blood pressure, heart rate, respiratory rate) will be monitored and collected post NanoDoce 
injection;  
• NanoDoce intravesical instillation;  
o 
Start time of instillation and time at end of void will be recorded; 
• Vital signs (blood pressure, heart rate, respiratory rate) will be monitored and collected post NanoDoce 
intravesical instillate (catheter removed and instillate voided); 


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• Collection of AE (start time of first NanoDoce injection) will be documented separately as treatment-
emergent adverse events (TEAE); 
• Collection of concomitant medication; 
• PK samples will be drawn at 1, 2, 6, and 24 hours post NanoDoce injection stop time; 
• Subject will be provided a diary to record AE and concomitant medications until the next study visit. 
 
7.3.4 VISIT 3 
Groups 1 and 2 
• 
One PK sample will be drawn. 
Group 2  
• Directed physical exam; 
• CBC and urinalysis sample collection  
o 
PK samples can be collected and processed at the same time as CBC samples.  
• AE review; 
• Concomitant medication review; 
• Review of eligible treatment options; 
• The Investigator will document all treatment options following review of subject records and institution 
standard of care protocols, and if it is determined that the subject is not a candidate for cystectomy or 
standard of care treatment, the Investigator will discuss with the subject the option of participating in the 
Group 2 Subset for Visits 4-9 Induction and Visits 10-12 Maintenance instillations, as an alternative choice.  
 
Group 2 Subset  
• Written informed consent including comprehensive discussion of the study schedule, procedures and 
subject protocol requirements may be conducted at any time from Visit 3 up to Visit 4 (prior to the first 
Induction instillation). 
7.3.5 INDUCTION PERIOD (VISITS 4 – 9) 
 
Only Group 1 and Group 2 subset subjects will complete the Induction Period (Visits 4-9). Subjects will be assessed 
for recovery (TURBT resection site healing) at Visit 4, at which point the Investigator will evaluate subject symptoms, 
pathology (if available), and gross hematuria or urinalysis findings. If the Investigator determines that the subject has 
not recovered at Visit 4, evaluations will be repeated at least every 2 weeks until the subject has recovered, at which 
time intravesical NanoDoce can be administered. 
At any time during the Induction Period, if intravesical instillation is delayed, the next instillation visits will be 
recalculated based on the new/rescheduled instillation date and per visit timelines and windows (see Schedule of 
Events: Table 2b).  
The 3-month Induction period will consist of 6 weekly NanoDoce intravesical instillation treatments, followed by 6 
weeks of rest. The following procedures will be performed: 
• Vital signs; 
• Directed physical exam; 


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• Sample collection and processing for clinical laboratory assessments (Section 7.2.1);  
o 
Non-clinically significant CBC and urinalysis must be confirmed prior to each intravesical 
instillation to rule out infection or DLT. A 48-hour window is allowed for sample collection and 
processing to ensure results are available prior to the intravesical instillation.  
o 
If applicable, chemistry, fibrinogen, aPTT, PT and PK samples can be collected and processed at 
the same time as CBC samples.  
o 
Visit 4 only: 
 
Chemistry, fibrinogen, aPTT and PT; 
 
PK samples will be drawn prior to NanoDoce instillation and at 1, 2, 6, and 24 hours 
post NanoDoce instillation stop time; 
o 
Visits 5-9: 
 
PK samples will be drawn prior to NanoDoce instillation; 
• Intravesical NanoDoce instillation (Section 6.1.5); 
• AE review; 
• Concomitant medication review; 
• In addition to the Visit 4 cystoscopy and cytology, at any time during the induction period, the Investigator 
may perform cytology, cystoscopy or biopsy (for positive or suspicious cytology or cystoscopic findings); 
o 
Any tissue sample collected will be processed according to Section 7.2.2.1; 
• Subject diary will be reviewed to confirm it is adequately completed. The subject will be questioned 
regarding discrepancies, missing entries and errors. Any discrepancy will be documented in the subject 
source documents by a delegated staff; and a new diary to be provided to the subject to record instillate 
void time and for daily completion to record adverse events and concomitant medications.  
 
7.3.6 MAINTENANCE PERIOD (VISITS 10 – 12) 
Only Group 1 and Group 2 subset subjects will complete the Maintenance Period (Visits 10-12). Visit 10 will occur 
after subjects complete the last day of the 3-month Induction period. If biopsy is indicated, maintenance therapy 
with NanoDoce is to be withheld until the histopathology results are available. NanoDoce intravesical instillation may 
be delayed up to 3 weeks.  
At any time during the Maintenance Period, if intravesical instillation is delayed, the next instillation visit will be 
recalculated based on the new/rescheduled maintenance instillation date and per visit timelines and windows (See 
schedule of Events: Table 2b).  
At Visit 10, subjects will proceed to a 3-month Maintenance period consisting of three NanoDoce intravesical 
instillations to be administered once weekly, in the first three weeks.  
 
The following procedures will be performed at Visits 10 - 12: 
• Directed physical exam may be performed; 
• ECOG – Visit 10 only; 
• Vital signs; 
• Sample collection and processing for clinical laboratory assessments (Section 7.2.1);  
o 
Chemistry, aPTT and PT at Visit 10 only 
o 
Non-clinically significant CBC and urinalysis must be confirmed prior to each intravesical 
instillation to rule out infection or DLT;  


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o 
A 48-hour window is allowed for sample collection and processing to ensure results are 
available prior to the intravesical instillation.  
o 
Chemistry, fibrinogen, aPTT, PT and PK samples can be collected and processed at the same 
time as CBC samples.  
• Intravesical NanoDoce instillations (Section 6.1.5); 
• PK samples will be drawn pre- NanoDoce instillation; 
• In addition to the Visit 10 cystoscopy and cytology, at any time during the maintenance period, the 
Investigator may perform cytology, cystoscopy or biopsy (for positive or suspicious cytology or cystoscopic 
findings); 
o 
Any tissue sample collected will be processed according to Section 7.2.2.1;  
• AE review; 
• Concomitant medication review; 
• Subject diary will be reviewed to confirm it is adequately completed. The subject will be questioned 
regarding discrepancies, missing entries and errors. Any discrepancy will be documented in the subject 
source documents by a delegated staff; and a new diary to be provided to the subject to record instillate 
void time and for daily completion to record adverse events and concomitant medications.  
 
7.3.7 END OF TREATMENT 
The End of Treatment visit (Visit 13) will be conducted after a subject completes the Day 1 NanoDoce injection and 
will always be conducted 45 days after the last study drug dose for early termination subjects, regardless of Group. 
For subjects completing the study, Visit 13 is conducted 180 days after Visit 4 for Group 1 and Group 2 Subset and 45 
days after Visit 2 for Group 2. If the End of Treatment visit is less than 45 days after the last NanoDoce instillation for 
Group 1 and Group 2 subset, due to instillation delays, a safety visit or phone call will be conducted 45 days after the 
last treatment to assess ongoing or new AEs. 
At the visit, the following procedures will be performed: 
• 
Comprehensive physical exam; 
• 
ECOG; 
• 
Vital signs; 
• 
12-lead ECG; 
• 
Clinical laboratory sample collection (Section 7.2.1);  
• 
PK Sample collection (one sample collection only); 
• 
Cystoscopy, urine cytology; 
• 
Biopsy; 
o 
Performed for positive or suspicious cytology or cystoscopic findings; 
o 
Any tissue sample collected will be processed according to Section 7.2.2.1; 
• 
AE collection; 
• 
Concomitant medication; 
• 
Subject diary will be reviewed to confirm it is adequately completed. The subject will be questioned regarding 
discrepancies, missing entries and errors. Any discrepancy will be documented in the subject source 
documents by a delegated staff.  


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7.3.8 SAFETY ASSESSMENT VISIT   
For early termination subjects, if the End of Treatment visit is not conducted, a follow up Safety visit will be 
completed to assess adverse reactions 45 days after the last study drug is administered (injection and/or instillation). 
The visit can be combined with the End of Treatment visit if both are conducted 45 days after the last study drug 
administration. During this visit the site will follow up on any existing AE and record any new AE or reactions as well 
as collect a PK sample  
7.3.9 EARLY TERMINATION VISIT 
 
In the event a subject is withdrawn, End of Treatment assessments, which include the procedures described in Section 
7.3.7, are expected to be completed. If a subject is withdrawn at a routine study visit, all evaluations expected at that 
study visit should be completed in addition to any procedure or evaluation listed in End of Treatment visit. Every effort 
should be made to inform the subject at the time of consent, that in the event of early termination, a last study visit 
will be completed, in addition to a visit for safety (see 7.3.8), so they are aware of expectations.  
7.3.10 SURVIVAL/PROGRESSION FOLLOW-UP  
 
  
Data will be collected for all subjects at 6 (Group 2 only), 9 and 12 months after Visit 4 to include progression, PFS 
and OS. Data will include concomitant therapy for bladder cancer (radiation, chemotherapy, immunotherapy and 
surgical intervention).  An additional subject visit will not be required as data will be collected by chart review. In 
cases where the subject has moved or lives in another city, data will be requested from the treating 
physician/institution. If the subject is no longer being followed by a treating physician/institution, a phone call may 
be conducted to determine survival and to collect the last post-study concomitant treatment data. This data will be 
collected for information only and will not be used to support a study endpoint. 
7.3.11 UNSCHEDULED VISITS 
Any unscheduled visits will be documented in the source documents, and any assessments and/or evaluations 
performed will be noted and reviewed. The subject will undergo any evaluations as determined necessary by the 
Investigator. All evaluations or procedures performed at the unscheduled visit, will be entered in the EDC.   


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7.3.10 SCHEDULE OF EVENTS TABLE 
 
Table 2a: Group 1 (NMIBC) and Group 2 Subset Schedule of Events 
 
Procedure 
Screening 
Treatment  
Induction  
Days      
(-30 - 0) 
Visit 2 
Visit 3 
Visit 4 1, 2 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Day 1 
Day 15 
(+/- 1 day) 
Day 1 
Week 1 
(> 4 weeks) 
Day 8 
Week 2 
(+/-2 days) 
Day 15  
Week 3 
(+/-2 days) 
Day 21 
Week 4 
(+/-2 days) 
Day 28  
Week 5 
(+/-2 days) 
Day 35 
Week 6 
(+/-2 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical and Surgical History3 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Physical Examination4 
X 
X5 
 
X 
X 
X 
X 
X 
X 
ECOG  
X 
X5 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
Vital Signs6 
X 
X 
 
X 
X 
X 
X 
X 
X 
Height and Weight 
X 
 
 
 
 
 
 
 
 
Pharmacokinetic Collection 
 
X7 
X7 
X7 
X8 
X8 
X8 
X8 
X8 
Laboratory Tests9 
X 
 
 
X 
X 
X 
X 
X 
X 
NanoDoce Direct Injection  
 
X 
 
 
 
 
 
 
 
NanoDoce Intravesical 
Instillation 
 
X 
 
X 
X 
X 
X 
X 
X 
TURBT10 
 
X 
 
 
 
 
 
 
 
Cystoscopy 10, 11 
X 
 
 
X 
 
 
 
 
 
Cytology 10, 11 
X 
 
 
X 
 
 
 
 
 
Biopsy,10, 11 
X 
 
 
X11 
 
 
 
 
 
Immunohistochemistry12 
 
X 
 
X 
X 
X 
X 
X 
X 
Diary Distribution 
 
X 
 
X 
X 
X 
X 
X 
X 
Diary Collection 
 
 
 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
 
X 
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
 
X 
X 
X 
X 
X 
X 
 Table 2 is continued on the next page. 
 


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Table 2b (Continued): Group 1 and Group 2 Subset Schedule of Events  
Procedure 
Maintenance 
End of Treatment  
 
Survival 
Follow-up 
   
Visit 10 
Visit 11 
Visit 12 
Day 85 
Week 13  
(+/-3 days) 
Day 92 
Week 14  
(+/-3 days) 
Day 99 
Week 15  
(+/-3 days) 
Day 180 
Visit 13  
(+/- 7 days) 
Months 9 & 
12 
Physical Examination4 
X 
X 
X 
X 
 
ECOG 
X 
 
 
X 
 
Vital Signs6 
X 
X 
X 
X 
 
12-Lead ECG 
 
 
 
X 
 
Laboratory Tests9 
X 
X 
X 
X 
 
NanoDoce Instillation 
X 
X 
X 
 
 
Pharmacokinetic 
Collection 7, 8 
X 
X 
X 
X 
 
Cystoscopy  10, 11 
X 
 
 
X 
 
Cytology  10, 11 
X 
 
 
X 
 
Biopsy 10, 11 
X 
 
 
X 
 
Immunohistochemistry11 
X 
X 
X 
X 
 
Diary Distribution 
X 
X 
X 
 
 
Diary Collection 
X 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
 
Concomitant Therapy 
X 
X 
X 
X 
X 
Survival 12 
 
 
 
 
X 
1. Start of Induction, or Visit 4, to be determined starting at 4 weeks post TURBT; If subject not recovered, evaluations will be repeated every 2 weeks until recovery confirmed.   
2. Group 2 subset will start induction treatment on the same schedule as Group 1 at Visit 4 
3. History includes all medical and surgical history prior to the first direct injection of NanoDoce; 
4. Comprehensive physical examination required at screening and End of Treatment; targeted physical exam at all other visits, if required; 
5. Comprehensive physical examination and ECOG to be performed at Visit 2 if not completed within the 14 days prior to Visit 2; 
6. Vitals will be performed prior to and post NanoDoce direct injection and intravesical instillations (see Section 7.3); Temperature measurement is not required during the Visit 2 Direct injection and 
instillation vitals monitoring; 
7. See Table 4 for Visits 2, 3 and 4 detailed PK collection schedule; 
8. PK samples will be collected within 24 hours prior to study drug intravesical instillation, or can be drawn to coincide with laboratory sample collection prior to the Induction and Maintenance 
intravesical instillation visit, if within allowable visit window; 
9. Laboratory testing (CBC and Urinalysis) to be performed and results reviewed prior to all Induction and Maintenance intravesical instillations. Chemistry and coagulation to be collected only at 
visits 1, 4, 10 and End of Treatment. Any tissue sample collected during the study will be processed per Institution pathology procedure;  
10. Cystoscopy and cytology required at Visits 4, 10 and End of Treatment; ad-hoc cystoscopy, urine cytology, and ‘for-cause’ biopsy can be conducted at any time during the study as needed, but 
must be  performed prior to any NanoDoce instillation; 
11. Any tissue sample collected during the study, starting with eligible TURBT tissue samples to be processed per Section 7.2.2.1; 
12. Chart review or subject contact. 


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Table 3: Group 2 (MIBC) Schedule of Events  
Procedure 
Screening 
Treatment 
End of Treatment  
Survival Follow-
up 
   
Visit 1 
Visit 2 
Visit 3 
Days (-30 - 0) 
Day 1 
Day 15  
(+/- 1 day) 
Day 45  
(+/- 5 days) 
Months 6, 9, 12  
Informed Consent 
X 
 
 
 
 
Medical and Surgical History1 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Physical Examination2 
X 
X3 
 
X 
 
ECOG  
X 
X3 
 
X 
 
12-Lead ECG 
X 
 
 
X 
 
Vital Signs4 
X 
X 
 
X 
 
Height and Weight 
X 
 
 
 
 
Pharmacokinetic Collection5 
 
X 
X 
X 
 
Laboratory Tests6 
X 
 
X 
X 
 
NanoDoce® Direct Injection  
 
X 
 
 
 
NanoDoce® Intravesical 
Instillation 
 
X 
 
 
 
TURBT 
 
X 
 
 
 
Cystoscopy 7 
X 
 
 
X 
 
Cytology 7 
X 
 
 
X 
 
Biopsy 7 
X 
 
 
X 
 
Immunohistochemistry8 
 
X 
 
X 
 
Diary Distribution 
 
X 
 
X 
 
Diary Collection 
 
 
 
X 
 
Adverse Events 
 
X 
X 
X 
 
Concomitant therapy 
X 
X 
 
X 
X 
Survival 9 
 
 
 
 
X 
1. 
History includes all medical and surgical history prior to the first direct injection of NanoDoce; 
2. 
Comprehensive physical examination required at screening and End of Treatment or early withdrawal; targeted physical exam at all other visits, if required; 
3. 
Comprehensive physical examination and ECOG to be performed at Visit 2 if not completed within the 14 days prior to Visit 2 
4. 
Vitals will be performed prior to and post NanoDoce direct injection and intravesical instillations (see Section 7.3); 
5. 
See Table 4 for detailed PK collection schedule; 
6. 
CBC and Urinalysis) to be performed and results reviewed prior to the Visit 2 Injection and the intravesical instillations. Chemistry and coagulation to be collected at visits 1 and End of 
Treatment; 
7. 
Any tissue sample collected during the study will be processed per Institution pathology procedure;  
8. 
Any tissue sample collected during the study, starting with eligible TURBT tissue samples to be processed per Section 7.2.2.1;  
9. 
Chart review or subject contact. 


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Table 4: Schedule of Pharmacokinetic Sample Collection 
Timepoint 
 
Post Dose 
0 Hour 1  
1 Hour (+/-10 min) 
2 Hours (+/-10 min) 
6 Hours (+/-20 min) 
24 Hours (+/-30 min) 
Visit 2 2  
X 3 
X 
X 
X 
X 
Visit 3 2, 4  
X 
 
 
 
 
Visit 4 5  
X 6 
X 
X 
X 
X 
Visit 5-13 
X 
 
 
 
 
1. 
PK sample collection to occur prior to administration of study drug for Visit 2 and Visit 4, and during Visit 3 (where no study drug is administered); 
2. 
Groups 1 and 2; 
3. 
PK sample collection within 24-hours prior to the Visit 2 study drug direct injection or anytime during the screening period; 
4. 
Even though there is a 1-day window, every effort should be made to collect the Day 15 sample on Day 15.  
5. 
Group 1 and Group 2 subset only; 
6. 
PK sample collection within 24-hours prior to the Visit 4 study drug intravesical instillation; or can be drawn to coincide with laboratory sample collection prior to the 
Induction intravesical instillation. 


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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Sponsor acknowledges that injection of NanoDoce into the resected bladder tumor, including the anesthesia 
necessary for the injection, may qualify as a sensitive procedure and as such should be mentioned in this section.  
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
All concomitant prescription medications taken during study participation will be recorded on the case report forms 
(eCRFs). For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the eCRF are concomitant prescription 
medications, over-the-counter medications, and non-prescription medications taken by the subject while on study 
and historical medication which are continued to be taken while on study for existing condition, whether or not 
acute. 
Medications allowed in the study will include: local anesthetic gel for catheter placement, prophylactic antibiotics 
(pre-or post TURBT) for infection prevention, methylene blue or other staining agents to enhance diagnostic 
visualization procedures and institution SOC IV chemotherapy (if required following Visit 2 direct injection and 
intravesical instillation).   
Group 2 subset subjects may receive radiation concurrently during Visits 4-12 induction and maintenance, per 
institution standard of care.  
Although no interaction studies have been conducted using NanoDoce, docetaxel is a CYP3A4 substrate metabolized 
by cytochrome P450 isozyme CYP3A4 (Taxotere Package Insert). In vivo studies showed that the exposure of 
docetaxel increased 2.2-fold when it was co-administered with ketoconazole, a potent inhibitor of CYP3A4. Protease 
inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of docetaxel and drugs 
that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided.  
7.6 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES  
No precautionary medications, treatments, or procedures are included in this protocol; they may, however, be 
administered at the discretion of the Investigator, anesthesiologist, or the subject’s primary care provider or 
oncologist. All medications will be recorded. 
7.7 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
Any distending media (conductive fluids, nonconductive or non-electrolyte and gas) other than isotonic saline or 
sterile water, are not allowed.  
For subjects in Group 1, the use of chemotherapy, immunotherapy, or radiation therapy is prohibited during the 
Induction period (at Visit 4 or later) or anytime during the maintenance period.  
7.8 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
Dexamethasone or institution standard of care allergy prophylaxis may be administered, at the discretion of the 
investigator. 
Dexamethasone use suggested: 


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Visit 2: Subjects in Groups 1 and 2 will take one 4 mg dexamethasone tablet 12 hours before NanoDoce 
direct injection, one 4 mg dexamethasone tablet 1 hour before NanoDoce direct injection, and one 4 mg 
dexamethasone tablet 8 hours after NanoDoce direct Injection. As both direct injection and intravesical 
instillation are planned for Visit 2, the timing of dexamethasone pretreatment will be determined by the 
direct injection dose only.  
Induction and Maintenance Intravesical Instillations: Subjects in Group 1 and Group 2 subset will take one 4 
mg dexamethasone tablet 12 hours before NanoDoce intravesical instillation, one 4 mg dexamethasone 
tablet 1 hour before NanoDoce intravesical instillation, and one 4 mg dexamethasone tablet 8 hours after 
NanoDoce intravesical instillation.  
Prophylactic antibiotics and any other prophylactic medications will be administered according to the institution’s 
SOC at any time during the study. 
7.9 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
Rescue medications, treatments, and procedures are not expected for this study. 
7.10 
PARTICIPANT ACCESS TO STUDY DRUG AT STUDY CLOSURE  
Not applicable. 
8 
ASSESSMENT OF SAFETY 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
Safety assessments to be conducted in this study include: 
• 
AE, collected at all study visits from the time of first study drug dose; 
• 
Changes in concomitant medications;  
• 
Findings from physical examinations; 
• 
Changes in vital signs; and 
• 
Changes in laboratory parameters. 
Safety will be reviewed by the Medical Monitor in an ongoing manner via the EDC system, and details will be 
confirmed at routine on-site monitoring visits.  
Safety and tolerability will be assessed by the DSMB prior to any dose escalation occurring.   
Included in the DSMB’s review of the AEs and general study data pertaining to safety there will be rules for non-
escalation. Any AE that is considered related or probably related to NanoDoce is potentially a DLT. The definition of a 
DLT will be made by consensus by the Medical Monitor, Sponsor Medical Director, and Principal Investigator for AEs. 
Events of special interest (Section 8.4.4) will be specifically reviewed and will form part of the review between doses, 
and the DSMB review will provide and document oversight as detailed in the DSMB Charter. 


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8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product that which does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended change in structure, function, sign, or symptom 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 a physical exam that was not included in the medical history. Clinical conditions 
attributable to disease progression will be considered AEs.  
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
A Serious Adverse Event (SAE) is any adverse event that meets at least one of following criteria: 
1) Is fatal; 
2) Is life-threatening; in the opinion of the investigator, the subject was at substantial risk of dying at the time 
of the adverse event, or use or continued use of the medical product might have resulted in the death of the 
patient; 
3) Is a persistent or significant disability or incapacity; 
4) Requires hospitalization or prolongs an existing hospitalization. Hospitalization will be defined as such if > 24 
hours, or a hospitalization that requires an intervention to treat emergent symptomatology (non-
diagnostic); 
5) Exposure prior to conception or during pregnancy may have resulted in a congenital anomaly or birth defect 
in the child; 
6) Other important medical events not noted in events above, but may be considered a serious experience 
when, based upon appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes as listed in #1-5 in this definition. 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
As this is a Phase 1/2 study, all unanticipated problems will be captured as either AEs or SAEs and will be defined and 
reported accordingly. 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 SEVERITY OF EVENT 
Signs and symptoms will be graded by the Investigator as mild, moderate, severe, life-threatening, or fatal according 
to the following definitions: 
• 
Mild:  The AE is transient and does not interfere significantly with the subject’s normal functioning level. The 
AE resolves spontaneously or may require minimal therapeutic intervention; 
• 
Moderate:  The AE produces limited functional impairment and may require therapeutic intervention. The 
AE produces no sequelae; 
• 
Severe:  The AE results in significant impairment of function and may lead to temporary inability to resume 


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the subject’s normal life pattern. The AE produces sequelae which require prolonged therapeutic 
intervention; 
• 
Life-Threatening:  The AE results in life-threatening consequences, urgent intervention is indicated, urgent 
operative intervention is indicated or the patient is at risk of death at the time of the event if immediate 
intervention is not undertaken; 
• 
Fatal:  The AE results in death. 
Further, toxicities should be evaluated according to the NCI CTCAE, version 4.0 criteria.  
8.2.2 RELATIONSHIP TO STUDY DRUG 
 
The following five-point scale will be used by the Investigator to rate the relationship of the AE to the study drug: 
 
• 
Definitely related: A clinical event (including laboratory test abnormality) occurring in a plausible time 
relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the drug (de-challenge) should be clinically plausible. The event 
must be definitively associated pharmacologically, using a satisfactory re-challenge procedure, if necessary;  
 
• 
Probably related: A clinical event (including laboratory test abnormality) with a reasonable time sequence to 
administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and 
which follows a clinically reasonable response on withdrawal (de-challenge). Re-challenge information is not 
required to fulfill this definition; 
 
• 
Possibly related: A clinical event (including laboratory test abnormality) with a reasonable time sequence to 
administration of the drug, but which could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear; 
 
• 
Unlikely to be related: A clinical event (including laboratory test abnormality) whose temporal relationship 
to drug administration makes a causal relationship improbable (e.g., the event did not occur within a 
reasonable time after administration of the trial medication) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical condition, other 
concomitant treatments); 
 
• 
Not related: An event for which sufficient information exists to conclude that the etiology of the event is 
unrelated to the study drug. An alternative definitive etiology should be documented by the Investigator. 
 
8.2.3 EXPECTEDNESS  
The definition of expectedness is related to the study drug specifically. An event may be unexpected in the subject 
but that in itself does not qualify as unexpected; review against information available and provided for the study 
drug is what will determine expectedness. 
Sponsor will be responsible for determining whether an AE is expected or unexpected. An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the study drug, in the protocol and within the Investigator’s Brochure. 


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8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
AE will be recorded throughout the study and at early termination and will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). Adverse events ongoing at the final study visit must be followed until resolution or 
until the Investigator determines them to be stable and/or adequately managed.  
Subjects will be required to spontaneously report any AEs. Study personnel will ask open-ended questions to obtain 
information about AEs at every visit. Date and time of onset and resolution (if applicable) of the AE will be 
documented. 
All SAEs must be followed until the event resolves or, in the opinion of the Investigator, become stable.  
The Sponsor will report any serious, unexpected and drug-related AE to applicable regulatory agencies and provide 
these reports to the investigative sites. The Investigator must promptly inform the IRB of such events and retain a 
copy of the notification in the Investigator Site File (ISF). 
8.4 
REPORTING PROCEDURES 
 
8.4.1 ADVERSE EVENT REPORTING  
AE will be captured from first study drug dose (injection) until 45 days after the last study drug dose (injection or 
instillation) for Group 2 subjects or until the End of Treatment (Visit 13) visit for Group 1 or Group 2 subset subjects. 
All AEs (whether or not attributable to the study drug) occurring during the study observed by the Investigator or 
reported by the subject will be recorded on the eCRF. The following information will be recorded for all AEs: 
• 
Event: name/condition/diagnosis/description; 
• 
Onset and resolution time and/or date; 
• 
Severity; 
• 
Relationship to study drug; (assessment by staff trained and authorized to diagnose), 
• 
Action taken; 
• 
Seriousness.  
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
All SAEs, including death, due to any cause which occurs during this study, whether or not expected and regardless of 
relationship to study drug, must be reported to the Medical Monitor immediately upon discovery of the event, using 
the SAE report form, by email or fax and, if necessary, by phone to: 
Dr. Antony Verco 
Medical Monitor 
E-mail: tony.verco@usbiotest.com 
Phone: 805-235-9193 
Fax: 805-980-4897 
 


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24-hour Emergency Contacts: 
Gere diZerega, MD 
or 
Antony Verco, MD 
 
Medical Director 
 
Medical Monitor 
 
805-630-2800  
 
805-235-9193 
The Sponsor will advise the Investigator regarding the nature of any further information or documentation that is 
required. The Investigator should provide the following documentation at the time of notification if available: 
• 
SAE Report Form; 
• 
Concomitant and support medication pages; 
• 
Relevant diagnostic reports; 
• 
Relevant laboratory reports; 
• 
Admission Notes; 
• 
Hospital discharge summary (when available). 
8.4.3 UNANTICIPATED PROBLEM REPORTING  
 
Unanticipated incidents or events that occur during the conduct of the study and meet the criteria for an AE or SAE 
will be captured in the source documents and in the EDC as such. See 8.4.1 and 8.4.2. 
 
8.4.4 EVENTS OF SPECIAL INTEREST  
Of particular interest will be signs of systemic toxicity due to docetaxel exposure; particularly from bladder injection. 
NanoDoce has never previously been injected in the bladder; subjects will be monitored for injection site pain and 
any reported event, in particular, during the first 36 hours after the procedure. 
8.4.5 REPORTING OF PREGNANCY  
A female patient is of childbearing potential unless she has had a hysterectomy, is at least one year postmenopausal, 
or has undergone tubal ligation. For the purposes of this study, all sexually-active patients must make use of double 
condoms until 45 days after the last study drug administration. 
Any pregnancy occurring in a subject or a subject’s sexual partner during the study or within 6 months after the last 
NanoDoce drug dose must be reported to US Biotest as soon as the Investigator is aware of it. The pregnancy will not 
be considered an SAE; however, information on the event will be collected and the outcome followed to birth or 
termination of pregnancy. 
Any pregnancy complication or premature terminations including miscarriage, spontaneous abortion, or elective 
termination of a pregnancy for medical reasons will be reported as an SAE, as described in Section 8.4.2. Should the 
pregnancy result in a congenital anomaly or birth defect, a separate SAE report must be submitted. Furthermore, all 
neonatal deaths that occur within 30 days of the birth should be reported as SAEs, without regard to causality. In 
addition, any infant death that occurs after the 30-day reporting period that the Investigator suspects is related to 
the in-utero exposure to the study treatment should also be reported. 
8.5 
STUDY HALTING RULES  
This study is a Phase 1/2 dose escalation study. Dose escalation will be determined following review of the safety and 
tolerability data in a cohort by the DSMB. Following review, at any time point, the study may be terminated. Should 
this occur, all subjects who have received treatment will be followed to the completion of the End of Treatment visit 


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or 45 days after administration of NanoDoce, whichever occurs later, to ensure all safety data is collected on all 
treated subjects. 
DSMB may determine that a further three subjects should be treated at the same dose as the current cohort, to 
provide additional safety and/or tolerability information as needed in order to determine if dose escalation should 
proceed; they may also determine that it is acceptable to proceed with an increased dose in the next cohort; or they 
may determine that the safety and tolerability profiles are not acceptable and may stop the study. 
The Sponsor is responsible for notifying FDA of any temporary halt to the study or when the study is terminated; the 
Investigator will be required to notify the IRB accordingly. 
8.6 
SAFETY OVERSIGHT 
Safety will be overseen by the Medical Monitor and the DSMB. 
All subject study data will be captured in an EDC system, allowing real-time access to ongoing safety and tolerability 
data. The Medical Monitor will perform ongoing data review for each subject entered in the database and prior to 
proceeding to dose escalation. See 10.4.7.1 
Prior to dose escalation proceeding, the DSMB will convene to review the cohort data, and generate a report 
outlining any safety concerns from the reviewed EDC data. This review will take place prior to proceeding with either 
addition of more subjects to a current cohort or proceeding to dose escalation in a new cohort. 
During the DSMB review, members will review all EDC safety data available; provided as reports generated directly 
from the EDC system and by the Data Management group. Emphasis will be placed on the events of special interest 
as outlined in Section 8.4.4, on emerging safety trends or events which may constitute dose limiting toxicities as 
outlined in Sections 6.1.7 and 8.1.  
9 
CLINICAL MONITORING 
US Biotest monitors, or delegates, will conduct scheduled site visits to the investigational centers for the purposes of 
monitoring the study. The Investigator agrees to allow monitors and other authorized Sponsor personnel or 
designees, access to the subject’s complete and comprehensive medical and research study records, Investigator Site 
File, pharmacy document and any other applicable documents as needed to assure that the conduct of the study and 
the safety of the study subject is maintained and within compliance. In addition, FDA or other government agencies 
may request an inspection, following notification to the site. In such an event, the Investigator agrees to notify the 
Sponsor immediately, or at the earliest possible opportunity of the request. The clinical trial site will allow access to 
the inspectors to review requested records. 
US Biotest will conduct a site initiation visit to provide the Investigator and study staff with a comprehensive 
overview of the protocol and study procedures and to review mutual obligations and requirements of regulatory 
authorities. The Investigator Site File (may be identified as regulatory file or binder) containing required 
documentation will be up to date throughout the life of the study and maintained at the site for reference and 
inspection. 
Routine monitoring visits will be conducted to assure compliance with the study protocol and regulatory 
requirements, to review and verify the subject’s eCRF by comparing with source documents, to ensure adequate 
records of clinical supplies are maintained, and to assess the continued suitability of the investigational site. On 


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completion of the study, the monitor will conduct a final visit to assess the conduct of the study, inform the 
investigator of ongoing and final regulatory obligations and perform a final inventory of all clinical supplies to be 
either returned to US Biotest, destroyed or retained at the site. 
 
10 STATISTICAL CONSIDERATIONS  
 
10.1 
STATISTICAL AND ANALYTICAL PLANS 
A formal Statistical Analysis Plan (SAP) will be prepared for this trial, and the SAP will be signed off prior to study 
database lock. 
10.2 
STATISTICAL HYPOTHESES 
No formal statistical inference (i.e., “p-values”) will be applied. The results of this trial will be based on descriptive 
statistics only. 
10.3 
ANALYSIS DATASETS 
In this safety and tolerability trial, all subjects who are enrolled and receive at least one dose of study drug will be 
included in the descriptive analysis.  
The dose populations will be defined in the SAP once the pattern of exposure is determined i.e. the dose and the 
total number of treatments.  The medical team will provide guidance on the groupings.  The resulting displays will 
provide the basis for interpreting possible dose-response outcomes for both safety and any possible signals of 
efficacy.  This will be supported by pharmacokinetic information where available. 
10.3.1 MISSING DATA 
Data will be presented as observed and no missing data imputation will be performed. All effort will be made to 
capture sufficient information to allow for medical interpretation of the results. 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 GENERAL APPROACH 
The focus of the trial will be on the safety and tolerability of the dose-escalated treatments. The general approach 
will be to highlight any trends that cause concern for the reviewing medical monitoring team (i.e., dose-limiting 
toxicities-DLTs).  
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Not applicable. The primary objective is to evaluate the safety and tolerability as demonstrated by AE, changes in 
laboratory assessments, physical examination findings and vital signs.  


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10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Secondary endpoints will be summarized descriptively. These will include supportive information to provide context 
for the dose(s) chosen to move forward for future study, as follows:  
• 
Concentration of docetaxel in the systemic circulation post-injection in the presence of intravesical 
instillation (as determined by PK analysis); 
• 
Disease progression as defined by cystoscopy, cytology, and if indicated, biopsy at Visit 10 (Group1 and 
Group 2 subset) and Visit 13  in Group 1 or Group 2 subset.  
• 
OS will be determined for all groups at Months 6 (Group 2 only), 9 and 12. 
See also Section 10.4.11, Exploratory Analyses, for further details. 
10.4.4 SAFETY ANALYSES 
 
10.4.4.1 
ADVERSE EVENTS 
AE recorded during the trial will capture medically relevant changes found during the physical exam, and medically 
relevant changes in vital signs and laboratory analytes found during the trial. In addition, spontaneously reported or 
observed events will be recoded 
Events reported at or after the first injection of NanoDoce will be considered TEAE. All reported events will be listed 
by subject number and assigned treatment, investigator term, MedDRA coded term, date/study day (from initial 
treatment) for onset and cessation, severity (using the NCIC severity grading), and relationship to study medication. 
Only the TEAE will be tabulated.  
The primary safety analysis and clinical study report will be based on the data collected up to the End of Treatment 
visit. Additional tabulations including safety data up to and including the 6-month follow-up visit will also be presented. 
The focus of the summary will be on the treatment/dose group for the subject. 
Adverse event reports will be coded using the most recent version of MedDRA, signed off by the Medical Monitor, 
and presented by system organ class and preferred term. All AE and abnormal laboratory variables will be assessed 
according to the NCI-CTCAE v4.0 grading system. The number of subjects reporting, and number of events reported 
will be presented in frequency tables (overall, by intensity, by relationship and by outcome) for each dose cohort in 
each group. Adverse events of special interest will be presented separately. The criteria for the most frequently 
reported events will be determined in the SAP after reviewing the data; due to the small dose cohorts, the traditional 
5 and 10% would not be reasonable.  
10.4.4.2 
LABORATORY ANALYTES 
Quantitative laboratory data will be summarized as mean values and change from screening scores (i.e., change = 
time point-screening) presented by dose level for each sampling time point. For tests with normal range provided, 
the clinical status and its change from screening (Normal/High Abnormal/Low Abnormal) will be summarized using 
shift tables for each dose group. Analytes of interest (e.g., hematological tests) may be graphed by subject with the 
dose indicated; these special analytes will be confirmed in the SAP. 


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10.4.4.3 
VITAL SIGNS 
Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate (if measured by the institution), 
temperature) and body weight will be tabulated and mean raw values and changes from baseline scores (change = 
baseline-visit) where baseline is the last measurement prior to the study drug application, for each treatment group. 
10.4.4.4 
ECOG 
The ECOG scale will be tabulated by treatment dose using shift tables to summarize and highlight change in category 
across the visits. 
10.4.5 ADHERENCE AND RETENTION ANALYSES 
All subjects who enter the trial will be accounted for and any reasons for early termination noted, including disease 
progression.  
10.4.6  BASELINE DESCRIPTIVE STATISTICS 
Complete demographic and baseline data will be tabulated. The medical history, which will be coded in MedDRA, will 
be presented. The disease history data, with a focus on the previous treatment and current staging, and the 
information collected on the procedure to apply the treatment will also be summarized.  
10.4.7 PLANNED INTERIM ANALYSES  
There are no formal interim analyses planned. There will be an ongoing safety and tolerability review by the Medical 
Monitor and regular DSMB meetings between cohorts in each group.  
10.4.7.1 
SAFETY REVIEW 
Safety data will be reviewed in a combination of Medical Monitor reviews and DSMB (based on the DSMB charter) 
meetings. Safety reviews will be conducted on an ongoing basis to allow for ‘real-time’ safety assessment.  
Group 1:  
Reviews will be conducted by the Medical Monitor for all clinical data from subjects in each cohort, on an ongoing 
basis and once each subject has completed Visit 4, Visit 6, and Visit 9. Additionally, depending on enrollment rate, 
during direct injection escalation phase, the Medical Monitor will conduct monthly reviews if more than 6 weeks 
between reviews occurs or is likely to occur. During the maintenance phase the Medical Monitor will conduct 
monthly reviews. At the end of Visit 9 for each cohort and at every 3 months during the maintenance period, the 
Medical Monitor will also provide an aggregate data report to the DSMB. A formal DSMB meeting will be conducted, 
at any time during the study if required or requested by any DSMB member following review of any data provided by 
the Medical Monitor.  
Dose escalation in Group 1 will proceed independent of Group 2 and according to the planned schedule in order to 
allow adequate safety assessment of multiple intravesical instillates.  
At the 1st safety review, all clinical data from each subject, in each cohort, including all DLTs (See section 8.1) and 
excluding PK, will be reviewed and evaluated to determine if the dose is safe and tolerable, up to and including the 
first day of the induction period instillation, or Visit 4. The Medical Monitor will provide an aggregate summary 


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report to the DSMB for review and approval for each subsequent direct injection dose escalation (Cohorts 2, 3 and 4). 
At the 2nd review, all clinical data from each subject in that cohort, including all DLTs (Section 8.1) and excluding PK, 
will be reviewed and evaluated up to, and including the fourth induction period instillation, or Visit 6. This will allow 
an assessment of safety prior to increasing the intravesical instillation dose from 2.0 mg/mL to 3.0 mg/mL,  
 
Group 2 
Monthly reviews will be conducted by the Medical Monitor for all clinical data from subjects in each cohort, on an 
ongoing basis. Safety evaluation for Group 1, depending on differing rates of enrollment between Groups 1 and 2, 
may be used as the basis for dose escalation in Group 2. In the event that the 3rd subject in a Group 2 cohort reaches 
Day 45 before the same dose is evaluated in Group 1, the dose escalation in Group 2 will be based on the relevant 
clinical data available in that Group 2 cohort.  
Groups 1 and 2 
In addition, the Medical Monitor will provide an aggregate data report to the DSMB every 3 months. A formal DSMB 
meeting will be conducted, at any time during the study if required or requested by any DSMB member following 
review of any data provided by the Medical Monitor.  
10.4.7.2 
EFFICACY REVIEW 
Cystoscopy and biopsy (if available), and any institution-required diagnostic imaging will be reviewed at End of 
Treatment visit for Group 1 and Group 2 subset. For Groups 1 and 2, histologic evaluation of tissue samples will be 
assessed for presence of tumor, if any.  Review may be earlier if there is persistence, recurrence and progression of 
disease.  
10.4.8 ADDITIONAL SUB-GROUP ANALYSES 
Subjects who perform particularly well (i.e., experience minimal AEs) may be compared to those who perform more 
poorly. This topic, and the criteria for defining each group, will be detailed in the SAP. 
10.4.9 MULTIPLE COMPARISON/MULTIPLICITY 
Not applicable, as no inferential analyses will be employed.  
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA 
All data collected in the eCRF will at a minimum be listed; listings will support the tabulated data/outcomes.  
10.4.11 
EXPLORATORY ANALYSES 
Determination of immune response in the bladder lesion due to NanoDoce injection and instillation by IHC staining 
will be evaluated for all positive tissue/biopsy samples at any time during the study; baseline TURBT samples will be 
concurrently evaluated. 
 
10.4.12 
CONCOMITANT MEDICATION 
All medication taken during the trial will be, at a minimum, listed with the start and stop dates. For this small clinical 
trial, the medications will not be coded using the WHO Drug Dictionary. 


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10.5 
SAMPLE SIZE 
There is no formal sample size calculation for this Phase I/II safety study. To provide a reference for the ongoing 
safety review of each cohort and the possible expansion of a cohort with safety concerns, the procedure “confidence 
interval for the probability of observing a rare event”  was employed in nQuery Advisor (Version 8) to determine 
that, for an event with an occurrence rate of 0.33, the probability of detecting it with 3 subjects is 69.9% vs 91.0% for 
6 subjects, and for an event rate of 0.05 the probability of detecting the event is 14.3% and 26.5% for 3 and 6 
subjects, respectively. 
The rationale to expand the final cohort in the Dose Confirmation Phase to 12 subjects, from either 3 or 6 subjects, 
was based on the “reasonable gain” in detection rate that each additional subject would provide in this early phase 
exploratory trial. The calculations were performed as the estimates above. With 12 subjects, the probability of 
detecting the 0.1 event rate is 71.8%, as compared to a 46.9% probability with 6 subjects. This sample size also allows 
for more acceptable probabilities of detecting much rarer events: for example, a 46% probability of detecting an 
event with a 0.05 event rate (compared to 26.5% with 6 subjects), and a 11.4% probability for an event with a 0.01 
event rate (5.9% with 6 subjects).    
10.6 
MEASURES TO MINIMIZE BIAS 
 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
Not applicable. 
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
Not applicable. 
10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
Not applicable.  
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
An eCRF is required and must be completed for each consenting and enrolled subject by qualified and authorized 
personnel. All data in the eCRF must reflect the corresponding source document. Any correction to eCRF entries 
must be reflected in a validated audit trail. Only data required by the protocol for the purposes of the study should 
be collected within the EDC. 
The Investigator must maintain adequate and accurate source documents on which the eCRFs for each subject are 
based. They will be separate and distinct from the eCRFs. These records should include detailed notes on: 
• 
The medical history prior to the subject’s involvement in the study; 
• 
Date of informed consent; 
• 
The basic identifying information that links the subject’s medical record with the eCRFs; 
• 
Screening, enrollment, end of treatment and safety visit details including dates and reasons for early 
termination; 
• 
The results of all diagnostic tests performed, diagnoses made, therapy provided, and any other data on the 


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condition of the subject; 
• 
The medical condition during the subject’s involvement in the study; 
• 
All AEs; 
• 
The subject’s exposure to the study medication; 
• 
The subject’s exposure to any concomitant therapy; 
• 
All relevant observations and data on the condition of the subject throughout the trial; 
• 
Justification for all entries in the subject’s eCRF.  
12 QUALITY ASSURANCE AND QUALITY CONTROL 
Data required by the protocol will be collected and entered into a validated data management system that is 
compliant with all regulatory requirements. The eCRF is an electronic document designed to record all 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 in the eCRF. The PI or designee, as identified 
on form FDA 1572, must electronically sign the completed eCRF for each participating subject to attest to its 
accuracy, authenticity, and completeness. 
The EDC application being used in this study is TrialMaster® version 4.2.1 from OmniComm Systems. TrialMaster 
studies are hosted from a state-of-the-art data center with rigorous physical and electronic security. All data is 
backed up daily to Iron Mountain, in Ohio and is also backed up to a hurricane-proof bunker in Fort Lauderdale, 
Florida. OmniComm has is certificated with European “Safe Harbor” regulations (all necessary measures are in place 
to protect patient confidentiality even with the data being stored in a US data center). The data management and 
statistical CRO, McDougall Scientific Ltd., ensures that the development of the eCRF follows their SOPs which are 
based on the Systems Development Life Cycle (SDLC) methodology. Access to the system is restricted by username 
and password; these are controlled by the Data Management CRO. All personnel using the system will be trained and 
the training documented. All changes to the database are recorded in an audit trail. The database will be locked 
when all outstanding queries have been addressed, all agreed-to data is marked as source-verified, and the PI has 
signed off on the eCRF contents.  
All software applications used in the collection of data will be properly validated following standard computer system 
validation that is compliant with all regulatory requirements.  
13 ETHICS/PROTECTION OF HUMAN SUBJECTS  
 
13.1 
ETHICAL STANDARD  
The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki. Sponsor and 
Investigator will comply with their responsibilities as defined in 21 CFR 312.50-312.70. 
13.2 
INSTITUTIONAL REVIEW BOARD  
Before the start of the study, the study protocol, informed consent form and/or other appropriate documents will be 
submitted to the IRB and/or the authorities in accordance with local legal requirements. It is the responsibility of the 
Investigator to assure that all aspects of the IRB review are conducted in accordance with current regulations. US 


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Biotest and the Investigator must inform each other in writing that all ethical and legal requirements have been met 
before the first subject is enrolled in the study. 
Amendments to the protocol will be subject to the same requirements as the original protocol. All changes to the 
consent form will be IRB-approved; a determination will be made regarding whether previously consented 
participants need to be re-consented by the IRB. 
13.3 
INFORMED CONSENT PROCESS  
 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Subjects being considered for participation in this study will be provided an informed consent form (ICF) to read and 
sign before being permitted to participate. The ICF will describe the study drug and any prior findings from previous 
studies; study procedures including the timing of study clinic visits and responsibility to adhere to those timelines; 
any risks which may be associated with the study drug or the procedures being carried out in the study; and all other 
items required under 21 CFR Part 50.25.  
Subjects will be required to provide signed consent prior to the conduct of any study-related procedures. The 
Investigator is required to document the process for obtaining informed consent in the source notes. 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
The Investigator will obtain informed consent from each subject enrolled in the study, in accordance with the U.S. 
Food and Drug Administration (FDA) regulations 21 CFR 50.20 - 50.27 and the laws and regulations of the state in 
which the investigation is being conducted. The IRB must approve the ICF to be used at the study site. The 
Investigator will provide the Sponsor with written IRB or Ethics Committee approval, before the Investigator will be 
permitted to enroll subjects into the study. 
It is the responsibility of the Investigator to ensure that informed consent is obtained from the subject or legal 
representative before any activity or treatment is undertaken, which is not part of routine or SOC. This includes, but 
is not limited to, the performance of diagnostic or therapeutic procedures and the administration of study drug. 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. 
In the event a protocol is amended, the consent form may be revised to reflect those changes; in which case, 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, if required by the IRB. 
The terms of the consent and when it was obtained must also be documented in the eCRF. The original, signed 
informed consent document must be maintained on file at the study site and be made available for review during 
monitoring visits and site audits. 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
All local legal requirements regarding data protection will be enforced. All study findings and documents will be 
regarded as confidential. The Investigator and members of his/her research team must not disclose such information 
without prior written approval from US Biotest.  


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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 (if allowed by institution, local and/or state requirements), birth date, and subject number. 
The subjects will be informed that all study findings will be stored and handled in strictest confidence, according to 
legal requirements, and that authorized research Investigators and agents of the FDA, the NCI, and authorized 
personnel or delegates of US Biotest have the right to inspect their medical records. 
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
Samples and data collected under this protocol are specifically for use in the evaluation and analyses conducted in 
the study. Samples will not be available for purposes other than as indicated within this protocol. No genetic testing 
will be performed. 
Access to stored samples will be limited to site authorized personnel authorized in the conduct of collecting, 
processing, storing and shipping to the designated laboratory for analysis. Samples will be stored using codes 
assigned by the Sponsor or as required by the clinical laboratory.  
Samples will only be retained until analyses are complete, after which they will be disposed of according to the 
laboratory SOPs. No samples will be retained for any future use. 
Data will be kept in password-protected computers. Only Investigators and those delegated responsibility on the 
Delegation of Authority Log will have access to the samples and data. 
13.5 
FUTURE USE OF STORED SPECIMENS  
Not applicable.  
14 DATA HANDLING AND RECORD KEEPING  
 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. The 
Investigator is responsible for ensuring the data is ALCOAC compliant.   
For electronic source, the institution must provide a secure, validated electronic medical record (EMR) data 
management system that is 21CFR Part 11 compliant and meets all regulatory requirements, regulations and quality 
standards. 
For paper source, documentation is expected to be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black or blue ink is required to ensure clarity of reproduced copies.  
Source documents will be maintained for recording data for each participant enrolled in the study. Data reported in 
the eCRF derived from source documents should be consistent with the source documents. Any discrepancies should 
be explained and captured in a progress note and maintained in the subject’s official electronic study record. 


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14.2 
STUDY RECORDS RETENTION  
The Investigator must retain a copy of all study documents in accordance with FDA or local regulations, whichever 
are the more stringent. 
The Investigator must maintain study documents: 
• 
For a minimum of two years following the date the marketing application (NDA) is approved for the 
indication for which the drug was investigated;  
• 
For a minimum of two years following the release date of the final report, if no marketing application is to 
be filed, or if the marketing application is not approved for the indication of which the drug was 
investigated or is discontinued, and FDA has been notified; or, 
• 
For a minimum of 15 years after the completion or discontinuation of the study to be filed in support of the 
registration in the European Union. 
If the Investigator relocates, retires or withdraws from the study for any reason, the study records may be 
transferred to an acceptable designee, such as another Investigator, another institution, or the Sponsor. The 
Investigator must obtain the Sponsor’s written permission before transferring or disposing of any records. 
14.3 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice (GCP), or FDA or IRB 
requirements. The noncompliance may be on the part of the participant, the Investigator, or the study site staff. As a 
result of deviations, corrective actions are required and expected to be implemented promptly by the site. 
These practices are consistent with ICH E6:  
 
• 
4.5:  Compliance with Protocol, Sections 4.5.1, 4.5.2, 4.5.3 and 4.5.4  
• 
5.1:  Quality Assurance and Quality Control, Section 5.1.1  
• 
5.20:  Noncompliance, Sections 5.20.1, and 5.20.2.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations as soon as possible 
after occurrence. All deviations must be addressed in study source documents, and reported to the Sponsor, the 
Data Management group and to the local IRB, per guidelines. The site PI/study staff is responsible to adhere to any 
IRB reporting requirements.  
Serious site non-compliance and an inability of the Sponsor to bring the site back into compliance, will be reported to 
FDA in accordance with their requirements.  
14.4 
PUBLICATION AND DATA SHARING POLICY 
By signing the study protocol, the Investigator agrees with the use of results of the study for the purposes of national 
and international registration, publication, and information for medical and pharmaceutical professionals. If 
necessary, the authorities will be notified of the Investigator's name, address, qualifications, and extent of 
involvement. The Sponsor will prepare an integrated clinical/statistical report. Publication/presentation of data is not 
allowed without explicit permission from US Biotest, Inc. Submission of data for publication/presentation will be 
coordinated and approved by US Biotest in collaboration with the Investigator. 


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The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical trials 
registration policy as a condition for publication. The ICMJE defines a clinical trial as any research project that 
prospectively assigns human subjects to intervention or concurrent comparison or control groups to study the cause-
and-effect relationship between a medical intervention and a health outcome. Medical interventions include drugs, 
surgical procedures, devices, behavioral treatments, process-of-care changes, and the like. Health outcomes include 
any biomedical or health-related measures obtained in subjects or participants, including pharmacokinetic measures 
and AE. The ICMJE policy, and the Section 801 of the Food and Drug Administration Amendments Act of 2007, 
requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by 
the National Library of Medicine. Data entered to the ClinicalTrials.gov website will be in accordance with FDA 
requirements for this registration and for publication of study results on that site. 
15 STUDY ADMINISTRATION 
 
15.1 
STUDY LEADERSHIP 
The study will be overseen by the Sponsor Study Lead or designee who will be responsible, together with the 
Investigators, for tracking enrollment, timelines, and deliverables, and other study-related performance. 
All questions regarding the enrollment of subjects, regulatory requirements for the conduct of the study, safety 
reporting, or study conduct should be addressed to the Site Monitor designated by the Sponsor. 
16 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical and therefore any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation 
in the trial. As required by FDA, a Financial Disclosure Form will be completed by each person noted on the form FDA 
1572 for this study, filed at the site and by the sponsor in the Trial Master File. 
17  LIABILITY AND INSURANCE  
The Sponsor will take out reasonable third-party liability insurance coverage in accordance with all local legal 
requirements. This insurance will cover all parties involved in the trial including, but not necessarily limited to, the 
principal investigator, clinical trial site, and subjects.  
 
 


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18  LITERATURE REFERENCES  
Albany C., Sonpavde G. Docetaxel for the treatment of bladder cancer. Expert Opin Investig Drugs. 2015;24(12):1657-
64. 
 
Babjuk M., Bohle A., Burger M., Capoun O., Cohen D., Comperat E. M., et al. EAU Guidelines on Non-Muscle-invasive 
Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 2017 Mar;71(3):447-61. 
 
Babjuk M., Böhle A., Burger M., Compérat E., Kaasinen E., Palou J., et al. Guidelines on non-muscle-invasive bladder 
cancer (TaT1 and CIS). 2015. 
 
Barlow L. J., Benson M. C. Experience with newer intravesical chemotherapy for high-risk non-muscle-invasive 
bladder cancer. Curr Urol Rep. 2013 Apr;14(2):65-70. 
 
Barlow L. J., McKiernan J. M., Benson M. C. The novel use of intravesical docetaxel for the treatment of non-muscle 
invasive bladder cancer refractory to BCG therapy: a single institution experience. World J Urol. 2009 Jun;27(3):331-
5. 
 
Barlow L. J., McKiernan J. M., Benson M. C. Long-term survival outcomes with intravesical docetaxel for recurrent 
nonmuscle invasive bladder cancer after previous bacillus Calmette-Guerin therapy. J Urol. 2013 Mar;189(3):834-9. 
 
Barlow L., McKiernan J., Sawczuk I., Benson M. A single-institution experience with induction and maintenance 
intravesical docetaxel in the management of non-muscle-invasive bladder cancer refractory to bacille Calmette-
Guerin therapy. BJU Int. 2009 Oct;104(8):1098-102. 
 
Dinney C. P., Greenberg R. E., Steinberg G. D. Intravesical valrubicin in patients with bladder carcinoma in situ and 
contraindication to or failure after bacillus Calmette-Guerin. Urol Oncol. 2013 Nov;31(8):1635-42. 
 
Hollister D., Jr., Coleman M. Hematologic effects of intravesicular thiotepa therapy for bladder carcinoma. JAMA. 
1980 Nov 7;244(18):2065-7. 
 
Laudano M. A., Barlow L. J., Murphy A. M., Petrylak D. P., Desai M., Benson M. C., et al. Long-term clinical outcomes 
of a phase I trial of intravesical docetaxel in the management of non-muscle-invasive bladder cancer refractory to 
standard intravesical therapy. Urology. 2010 Jan;75(1):134-7. 
 
Mak R. H., Hunt D., Shipley W. U., Efstathiou J. A., Tester W. J., Hagan M. P., et al. Long-term outcomes in patients 
with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis 
of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 
1;32(34):3801-9. 
 
McKiernan J. M., Masson P., Murphy A. M., Goetzl M., Olsson C. A., Petrylak D. P., et al. Phase I trial of intravesical 
docetaxel in the management of superficial bladder cancer refractory to standard intravesical therapy. J Clin Oncol. 
2006 Jul 1;24(19):3075-80. 
 
Oken M. M., Creech R. H., Tormey D. C., Horton J., Davis T. E., McFadden E. T., et al. Toxicity and response criteria of 
the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. 
Park J. C., Citrin D. E., Agarwal P. K., Apolo A. B. Multimodal management of muscle-invasive bladder cancer. Curr 
Probl Cancer. 2014 May-Jun;38(3):80-108. 
 
Smith Z. L., Christodouleas J. P., Keefe S. M., Malkowicz S. B., Guzzo T. J. Bladder preservation in the treatment of 
muscle-invasive bladder cancer (MIBC): a review of the literature and a practical approach to therapy. BJU Int. 2013 
Jul;112(1):13-25. 
 


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Steinberg G., Bahnson R., Brosman S., Middleton R., Wajsman Z., Wehle M. Efficacy and safety of valrubicin for the 
treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol. 
2000 Mar;163(3):761-7. 
 
Taxotere (docetaxel) Package Insert. Sanofi-aventis US LLC. Rev Dec 2015. 
 
TICE® BCG Package Insert. Organon USA Inc. Rev Feb 2009. 
 
 


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APPENDIX A: ECOG PERFORMANCE SCALE 
Patient performance status will be graded according to the Eastern Cooperative Oncology Group (ECOG) scale* as 
described below.  
 
Grade ECOG PERFORMANCE STATUS DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity and Response 
Criteria of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.  
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN (SAP) 
 
Phase 1/2 Trial Evaluating the Safety and Tolerability of 
NanoDoce® Injection and Intravesical Instillation in 
Subjects with Urothelial Carcinoma  
 
Protocol Number: 
NANODOCE-2017-02 
Study Phase  
I/II                          
Trial Design: 
Open-label, Single dose direct injection followed by intravesical instillations, 
3+3 Dose Escalation Study with both Dose-Escalation and Dose 
Confirmation Phases 
Medication/dosage: Nanodoce (Sterile Nanoparticulate Docetaxel) at concentrations of 0.75, 1.5, 
2.5, or 3.75 mg/mL in the direct injection dose and at concentrations of 2 or 3 
mg/mL for the intravesical instillation. 
Population 
Up to 75 male/female subjects with urothelial carcinoma (NMIBC or MIBC). 
Study/Treatment 
duration: 
Study duration will be up to 30 months.  
Group 1 and Group 2 Subset: Estimated up to 33 weeks.  
Group 2: Estimated up to 64 days.  
Follow-ups are scheduled up to 1 Year. 
Sponsor Contact 
Shelagh Verco 
US Biotest, Inc 
231 Bonetti Dr., Suite 240 
San Luis Obispo, CA 
93401-7310, USA 
 
Voice:  (805) 595-1300 
Fax:     (805) 595-1350 
e-mail: shelagh.verco@usbiotest.com  
Analysis Contact 
Jim Wang 
McDougall Scientific Ltd. 
789 Don Mills Road,  
Suite 802, Toronto, ON 
M3C 1T5 
Voice:  (416) 673-9470 
Fax:     (416) 424-2095 
e-mail:  jwang@mcdougallscientific.com 
 
 
Version: 
final 
 
Date: 
25-Nov-2021 


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SIGNATURE APPROVAL PAGE
1 of 2
Date of Final Protocol 
(including all amendments)
18-Jun-2020 v7.0
Date of Final Plan: 25-Nov-2021
I have reviewed the Statistical Analysis Plan. My signature below confirms my 
agreement with the contents and intent of this document.
Digital Signatures
Author:
Jim Wang, MA P.Stat
Senior Statistician, 
McDougall Scientific Ltd.
Reviewed by:
Hong Chen, MSc. P.Stat.
Chief Analytics Officer
McDougall Scientific Ltd.
Digitally signed by 
CHUNGUI WANG 
Reason: I am the author of 
this document 
Date: 2021.12.03 14:26:33 
-05'00'
Digitally signed by 
XIAOHONG CHEN 
Date: 2021.12.08 
17:26:25 -05'00'




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LIST OF ABBREVIATIONS AND TERMS ........................................................... 7 
1 
BACKGROUND ........................................................................................ 10 
2 
OBJECTIVES ........................................................................................... 11 
2.1 
Primary Objective ...................................................................................... 11 
2.2 
Secondary Objectives ............................................................................... 11 
3 
STUDY DESIGN AND ENDPOINTS ......................................................... 11 
3.1 
Study Design ............................................................................................. 11 
3.1.1 
Subject Groups ...................................................................................... 11 
3.1.2 
Dose Escalation Schedule ..................................................................... 12 
3.2 
Primary Endpoint ....................................................................................... 15 
3.3 
Secondary Endpoints ................................................................................ 15 
3.4 
Exploratory Endpoints ............................................................................... 15 
3.5 
Study Timeline and Schedule of Events .................................................... 16 
4 
DATA MANAGEMENT ............................................................................. 19 
4.1 
Data Collection and Database Construction ............................................. 19 
4.2 
Coding ....................................................................................................... 20 
4.3 
Pharmacokinetics (PK) Data ..................................................................... 20 
4.4 
Immunohistochemistry Data ...................................................................... 20 
5 
CHANGE TO ANALYSIS AS OUTLINED IN THE PROTOCOL .............. 20 
5.1 
Recurrence-Free Survival (RFS) ............................................................... 20 
5.2 
Additional Sub-Group Analysis.................................................................. 21 
6 
STATISTICAL METHODS ........................................................................ 21 
6.1 
Sample Size .............................................................................................. 21 
6.2 
Missing Data ............................................................................................. 22 


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6.3 
Data Conversion for Analysis .................................................................... 22 
6.4 
Calculated Outcomes ................................................................................ 22 
6.5 
Analysis Population ................................................................................... 24 
6.6 
Interim Analysis/ Data Monitoring .............................................................. 25 
6.7 
Analysis Methods ...................................................................................... 25 
7 
RESULTS ................................................................................................. 25 
7.1 
Study Subjects .......................................................................................... 26 
7.1.1 
Patient Disposition ................................................................................. 26 
7.1.2 
Demographics and Baseline Characteristics ......................................... 26 
7.1.3 
Medical History ...................................................................................... 26 
7.1.4 
TURBT ................................................................................................... 26 
7.1.5 
NanoDoce Administration ...................................................................... 26 
7.2 
Primary Outcomes .................................................................................... 26 
7.2.1 
Adverse Events ...................................................................................... 27 
7.2.2 
Laboratory Assessments ....................................................................... 27 
7.2.3 
Physical Examination ............................................................................. 28 
7.2.4 
Vital Signs .............................................................................................. 28 
7.2.5 
12-Lead ECG ......................................................................................... 28 
7.3 
Secondary Outcomes ................................................................................ 28 
7.3.1 
Plasma Docetaxel Concentration ........................................................... 28 
7.3.2 
Recurrence-Free Survival and Disease Progression ............................. 29 
7.3.3 
Overall Survival ...................................................................................... 29 
7.3.4 
Cystoscopy, Cytology, and Biopsy ......................................................... 29 
7.3.5 
Eastern Cooperative Oncology Group (ECOG) Performance Scale ...... 29 


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7.3.6 
Immunohistochemistry Data .................................................................. 29 
7.4 
Safety Outcomes ....................................................................................... 29 
7.5 
Other Outcomes ........................................................................................ 30 
7.5.1 
Prior and Concomitant Medications ....................................................... 30 
7.5.2 
Concomitant Procedures ....................................................................... 30 
Appendix A: ECOG Performance Scale .......................................................... 31 


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LIST OF ABBREVIATIONS AND TERMS 
 
Abbreviations 
Abbreviation 
Definition 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
APR 
Analysis Programming Requirements - detailed programming 
specifications required to convert the EDC data into 
analysis/presentation data sets. 
ATC 
Anatomical Therapeutic Chemical Classification System 
 
BLQ 
Below the Limit of Quantification / Below Limit of Quantitation 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DLC 
Data Logic Check- A combination of programmed and visual checks 
based on the CRF, protocol, and sponsor input, designed to identify 
incomplete or illogical data.  
DMP  
Data Management Plan - details of how data are managed 
throughout the trial 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
LLOQ 
Lower Limit of Quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities (coding for AEs) 
MIBC 
Muscle Invasive Bladder Cancer 


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Abbreviation 
Definition 
NMIBC 
Non-Muscle Invasive Bladder Cancer 
OS 
Overall Survival 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PT 
Preferred Term (from MedDRA coding dictionary) 
RFS 
Recurrence-Free Survival 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class (from MedDRA coding dictionary) 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
WHODD 
World Health Organization Drug Dictionary 
 
Definition of Terms 
Term 
Definition 
McDougall 
McDougall Scientific Ltd - CRO contracted to perform the data 
management, statistical programming and analysis functions 
NanoDoce 
Sterile Nanoparticulate Docetaxel. The investigational product. 
Cohort 
In this document, Cohort refers to dose level of direct injection of 
NanoDoce concentrations: 0.75, 1.5, 2.5, or 3.75 mg/mL.  
All treated subjects can be classified into one and only one Cohort. 


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Treatment 
Group 
In this document, Treatment Group refers to the combination of direct 
injection dose level and intravesical instillation dose level. There are 
eight planned Treatment Groups: 0.75/2.0, 0.75/3.0, 1.5/2.0, 1.5/3.0, 
2.5/2.0, 2.5/3.0, 3.75/2.0, 3.75/3.0 mg/mL. 
All treated subjects can be classified into one and only one 
Treatment Group, but some treatment groups may have no subject. 
 
 
 


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1 
BACKGROUND 
Bladder cancer is the sixth most common cancer in the United States, with an estimated 
79,030 new cases and 16,870 deaths from the disease predicted in 2017. Most patients 
(approximately 75%) with bladder cancer are diagnosed with disease confined to the 
mucosa or submucosa, classified as non-muscle invasive bladder cancer (NMIBC). 
Approximately 25% of patients with bladder cancer present with a tumor invading the 
muscle layer of the bladder wall. Muscle invasive bladder cancer (MIBC) is associated 
with a high rate of recurrence and poor overall prognosis despite aggressive local and 
systemic therapies.   
Investigational drug product NanoDoce (sterile nanoparticulate docetaxel) Powder for 
Suspension is being developed by NanOlogy, LLC (NanOlogy) for the treatment of NMIBC 
and MIBC. 
In this open-label, dose rising, phase 1/2 trial, subjects with high-risk NMIBC or MIBC, will 
receive NanoDoce (sterile nanoparticulate docetaxel) Powder for Suspension as a direct 
injection to the bladder wall and intravesical instillation(s). Subjects will be stratified into 
two treatment groups, Group 1 (NMIBC) and Group 2 (MIBC). At study treatment Day 1 
(Visit 2), all subjects will receive NanoDoce injected into the index tumor resection site on 
the bladder wall, immediately following transurethral resection of the bladder tumor 
(TURBT), followed by an initial NanoDoce intravesical instillation (within 2 hours of the 
direct injection).  
After assessment for recovery (TURBT resection site healing), subjects from Group 1 and 
a subset of Group 2 will move forward to the induction period and maintenance period with 
more NanoDoce intravesical instillations. Other Group 2 subjects will proceed to 
institutional standard of care treatments. 
The study will consist of a dose escalation phase and a dose confirmation phase for the 
direct injection of NanoDoce concentrations (0.75, 1.5, 2.5, or 3.75 mg/mL) for Groups 1 
and 2. In the direct injection dose escalation phase, subjects will be enrolled in sequential 
cohorts of three subjects starting at the lowest concentration.  
Following Data Safety Monitoring Board (DSMB) review of the cohort data, a 3+3 design 
will be applied to determine the most suitable direct injection dose for further evaluation. 
Additional subjects will be enrolled to provide up to a total of 9 subjects dosed at that dose 
level. 
The study will also dose escalate Groups 1 and 2 for the intravesical instillation of 
NanoDoce concentrations (2.0 and 3.0 mg/mL). The dose of intravesical instillation 


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depends on the study period (Day 1, induction period, or maintenance period) of each 
subject, and the study phase (dose escalation phase or dose confirmation phase). Please 
see details in section 3.1.2. 
2 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of NanoDoce 
injected directly into the bladder wall and instilled intravesically. 
2.2 
Secondary Objectives 
The secondary objectives are: 
x 
To characterize the PK of docetaxel when injected directly into the bladder wall, in 
the presence of NanoDoce intravesical instillation.  
x 
To determine whether any of the NanoDoce concentrations (0.75, 1.5, 2.5, or 3.75 
mg/mL) in the presence of NanoDoce intravesical instillation concentration dose of 
2.0 or 3.0 mg/mL, shows signs of preliminary efficacy.  
3 
STUDY DESIGN AND ENDPOINTS 
3.1 
Study Design 
This is a Phase I/II, open-label, dose rising trial with two phases: an initial dose escalation 
phase following a design like traditional 3+3 designs, and a dose confirmation phase with 
9 subjects enrolled at the most suitable dose determined in the dose escalation phase. 
3.1.1 
Subject Groups 
All subjects are stratified into two treatment groups based on disease status at enrollment: 
Group 1 (NMIBC) or Group 2 (MIBC). At Visit 2 (Study Day 1), all subjects will receive 
NanoDoce injected into the index tumor resection site on the bladder wall, immediately 
following transurethral resection of the bladder tumor (TURBT), followed by an initial 
NanoDoce intravesical instillation (within 2 hours of the direct injection).  
At Visit 3 (Study Day 15), a subset of Group 2 subjects, as determined by the treating 
investigator, who are deemed ineligible for cystectomy and intolerant to existing standard 
of care chemotherapy or treatment, may be offered intravesical chemotherapy in the 
Induction and Maintenance periods as described for Group 1 in this study (referred to 
hereafter as the “Group 2 Subset”). 


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Group 1 and Group 2 Subset subjects will have same schedule of visits and assessments. 
They will have 1) one direct injection followed by one intravesical instillation on Study Day 
1, 2) a 3-month Induction period consisting of 6 weekly NanoDoce intravesical instillations, 
followed by 6 weeks of rest, and 3) a 3-month Maintenance period, consisting of 3 weekly 
NanoDoce intravesical instillations, followed by 9 weeks of rest. 
Other Group 2 subjects (referred to hereafter as the “Group 2”) will proceed to institutional 
standard of care treatments after their direct injection and intravesical instillation on Day 
1. 
3.1.2 
Dose Escalation Schedule  
Direct Injection  
The study will consist of a dose escalation phase and a dose confirmation phase for the 
direct injection of NanoDoce concentrations (0.75, 1.5, 2.5, or 3.75 mg/mL) for Groups 1 
(NMIBC) and 2 (MIBC). 
During direct injection dose escalation, cohorts will be enrolled sequentially starting at the 
lowest concentration. Cohorts will enroll separately for Groups 1 and 2. Each cohort will 
have a planned minimum of three subjects for Group 1 and three subjects for Group 2. 
Following Data Safety Monitoring Board (DSMB) review of the cohort data, with the 
exception of the PK data, the DSMB will determine whether to:  
a) escalate to the next dose level cohort (no DLT);  
b) add three additional subjects to the current cohort (one DLT);  
c) if still at the first cohort, stop the study (2 or more DLT);  
d) if at higher cohorts, return to the previous (lower) dose cohort and expand by three 
subjects (more than one DLT).  
The dose determined to be most suitable for further evaluation, defined as the highest 
dose with an acceptable safety and tolerability profile (as determined by the DSMB) will 
enroll additional subjects to total up to 9 subjects at that direct injection dose level.  
Intravesical Instillation  
The study will also dose escalate Groups 1 and 2 for the intravesical instillation of 
NanoDoce concentrations (2.0 and 3.0 mg/mL). In the intravesical instillation dose 
escalation phase, all subjects in Group 1 will be enrolled at the lowest concentration of 2.0 
mg/mL for the Visit 2 (Study Day 1) instillation, i.e., the first instillation within 2 hours of the 
direct injection. If the dose is well-tolerated, Group 1 subjects will continue to receive 2.0 
mg/mL through Visit 6 (the 3rd instillation of the induction period), then escalate to 3.0 


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mg/mL intravesical instillations for the subsequent Induction and Maintenance intravesical 
instillations following ongoing data review by the Medical Monitor and the DSMB. Group 2 
subjects will be enrolled at the lowest concentration of 2.0 mg/mL for the Visit 2 instillation 
for all direct injection doses. If the dose is well-tolerated for the Group 1 subjects (following 
ongoing data review by the Medical Monitor and the DSMB), Group 2 and Group 2 subset 
subjects will escalate to 3.0 mg/mL intravesical instillations for the dose confirmation 
phase of the study.  
Escalation to 3.0 mg/mL in each group will proceed, independent of the other group. If no 
subjects in cohort 1 at 2.0 mg/mL experience a DLT, the intravesical dose will escalate to 
3.0 mg/mL for that group as described below. If two or more subjects in cohort 1 
experience a DLT at 2.0 mg/mL, then the study will stop. If one of the three subjects in 
cohort 1 experiences a DLT at 2.0 mg/mL, then an additional three subjects will be enrolled 
to cohort 1 at 2.0 mg/mL. If, in the additional three subjects at 2.0 mg/mL, no subjects 
experience a DLT, then the dose will remain at 2.0 mg/mL as described below. If >1 DLT 
occurs in the additional three subjects, the study will stop. 


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3.2 
Primary Endpoint 
The primary endpoint will be safety and tolerability, as demonstrated by adverse events 
(AE), changes in laboratory assessments, physical examination findings, and vital signs. 
3.3 
Secondary Endpoints 
The secondary endpoints will be:  
x 
Concentration of docetaxel in the systemic circulation post-injection in the 
presence of intravesical instillation (as determined by PK analysis);  
x 
PFS defined as tumor recurrence or disease progression at Visit 10 and Visit 13;  
x 
OS determined by survival time following NanoDoce injection.  
3.4 
Exploratory Endpoints 
The exploratory endpoints will be to determine whether exposure to NanoDoce will affect:  
x 
Tumor-specific antigens (IHC);  
x 
Immunophenotyping of T cells, B cells and monocytes  


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3.5 
Study Timeline and Schedule of Events 
Table 1: Group 1 (NMIBC) and Group 2 Subset Schedule of Events 
 
 
Table 1 is continued on the next page. 


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Table 1 (continued): Group 1 (NMIBC) and Group 2 Subset Schedule of Events 
 
 


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Table 2 Group 2 (MIBC) Schedule of Events 
 
 


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4 
DATA MANAGEMENT 
4.1 Data Collection and Database Construction 
Most data will be collected at the sites via an electronic data capture (EDC) system.  The 
study-specific application will be developed based on the protocol requirements and 
following the full Systems Development Lifecycle (SDLC).  The development and 
management of the trial application, including security and account administration, will 
adhere to the Standard Operating Procedures (SOPs) at McDougall.  All participants will 
be trained in the use of the application, and the training documented prior to each site 
being initiated. 
The application design will, where appropriate, provide choice fields in the form of 
checkboxes, buttons and lists to aid in ensuring high quality standardized data collection.  
In addition Data Logic Checks (or data Edit Checks) will be built into the application based 
on variable attributes (e.g. value ranges), system logic (e.g. sequential visit dates) and 
variable logic (e.g. onset date must be before cessation date).  Visual review and data 
responses will be overseen by a trained data manager. 
The database will be locked when all the expected data has been entered into the 
application, all query responses have been received and validated, the designated data 
has been noted as monitored in the system and each investigator has signed off the 
casebook for each of their study subjects. The data coding must be accepted by the 
Sponsor and any Serious Adverse Events (SAEs) reconciled with the pharmacovigilance 
data base working with the Medical Monitor. 
According to study design, following external/central lab data will not be entered into EDC 
system. They will be provided as external data: 
x 
Concentration of docetaxel in the systemic circulation 
x 
Immunohistochemistry data 
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 NA06NDH. 
All programming will be performed in SAS version 9.4 or higher. 


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4.2 
Coding 
Adverse Events and medical history will be coded in MedDRA version 22.0 and signed off 
by US Biotest, Inc. All concomitant medications will be coded using WHO Drug Dictionary 
Global C3 March 1, 2019. All coding will be reviewed and signed off prior to data base 
lock. 
4.3 
Pharmacokinetics (PK) Data 
The PK analysis of plasma docetaxel concentration will be performed by Covance 
Madison Laboratories Bioanalytical (BA) Group. The concentration data will be provided 
to McDougall in Excel data sheets to be read into SAS system for descriptive summaries. 
4.4 
Immunohistochemistry Data 
The immunohistochemistry data will be provided to the Sponsor by the external laboratory, 
NeoGenomics, for incorporation to the Clinical Study Report as an appendix or addendum.   
5 
CHANGE TO ANALYSIS AS OUTLINED IN THE PROTOCOL 
5.1 
Recurrence-Free Survival (RFS) 
Protocol section 4.2.2 describes a secondary endpoint: 
PFS defined as tumor recurrence or disease progression at Visit 10 and 
Visit 13  
Because of the different disease types and treatment schedules, the treatment efficacy 
will be assessed and analyzed differently for the two subject groups: 
Group 1 (NMIBC) 
Each subject’s Recurrence-Free Survival (RFS) time will be calculated: 
RFS time = months from direct injection to recurrence or death, if the subject had 
recurrence after initial TURBT, or died within Month 12 follow-up. 
= months from direct injection to cystectomy or last alive date if the subject 
did not have recurrence before cystectomy or last contact. 
RFS (yes/no) at Visits 10 and 13, as well as RFS time will be summarized by cohort and 
for total Group 1 subjects.  
Group 2 (MIBC) 


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Disease progression (yes/no) at Day 45 will be derived for all Group 2 subjects based on 
their cytology and biopsy assessments. It will be summarized by cohort and for total Group 
2 subjects.  
5.2 
Additional Sub-Group Analysis 
Protocol section 10.4.8 describes additional sub-group analysis: 
Subjects who perform particularly well (i.e., experience minimal AEs) may 
be compared to those who perform more poorly. This topic, and the criteria 
for defining each group, will be detailed in the SAP. 
To conduct subgroup analysis, either directly compare safety/efficacy between subgroups, 
or perform safety/efficacy analysis for one or more subgroups, the subgroup(s) should be 
defined by baseline information, and not by data collected during study conduct, such as 
AE, therefore, and in consideration of the small number of subjects in this study, these 
subgroup analyses will not be conducted.   
6 
STATISTICAL METHODS  
Descriptive summaries of continuous data will consist of the mean, standard deviation, 
median, minimum, and maximum. Categorical data will be summarized with frequencies 
and percentages. All data will be listed by subject and treatment. This study was not 
powered for inference, and so no inferential analyses will be included.  
6.1 
Sample Size 
There is no formal sample size calculation for this Phase I/II safety study. To provide a 
reference for the ongoing safety review of each cohort and the possible expansion of a 
cohort with safety concerns, the procedure “confidence interval for the probability of 
observing a rare event” was employed in nQuery Advisor (Version 8) to determine that, 
for an event with an occurrence rate of 0.33, the probability of detecting it with 3 subjects 
is 69.9% vs 91.0% for 6 subjects, and for an event rate of 0.05 the probability of detecting 
the event is 14.3% and 26.5% for 3 and 6 subjects, respectively.  
The rationale to expand the final cohort in the Dose Confirmation Phase to 12 subjects, 
from either 3 or 6 subjects, was based on the “reasonable gain” in detection rate that each 
additional subject would provide in this early phase exploratory trial. The calculations were 
performed as the estimates above. With 12 subjects, the probability of detecting the 0.1 
event rate is 71.8%, as compared to a 46.9% probability with 6 subjects. This sample size 
also allows for more acceptable probabilities of detecting much rarer events: for example, 
a 46% probability of detecting an event with a 0.05 event rate (compared to 26.5% with 6 


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subjects), and a 11.4% probability for an event with a 0.01 event rate (5.9% with 6 
subjects). 
6.2 
Missing Data 
Data will be presented as observed and no missing data imputation will be performed. All 
effort will be made to capture sufficient information to allow for medical interpretation of 
the results. 
6.3 
Data Conversion for Analysis 
To summarize quantitative endpoints, e.g., lab test results, some data collected as text 
values need to be converted to numeric values for analysis. Following conventional rules 
will be applied for this study. 
x 
All “< xx” lab results will be converted to 0.99 * xx. The adjustment is -1% of xx. 
x 
All “> xx” lab results will be converted to 1.01 * xx. The adjustment is +1% of xx. 
x 
Some PK concentration values may be marked as Below the Limit of Quantification 
(BLQ) or reported as “< xx”. Here xx is the Lower Limit of Quantitation (LLOQ). For 
the summary of docetaxel concentration in this study, all BLQ values will be set to 
0. 
Above data conversions are only applied to data descriptive summaries. In by-subject data 
listings, original reported data “< xx”, “> xx”, or “BLQ” will be presented. 
For this study’s data submission and analysis, all EDC and external data will be converted 
to SDTM (Study Data Tabulation Model) and ADaM (Analysis Data Model) datasets. In 
the creation of SDTM and ADaM datasets, original lab test results from different sites 
(laboratories) need to be converted to results in SI units (the International System of Units). 
For some tests, data rounding may be applied during the conversion. The details will be 
provided in SDTM and ADaM’s define.xml files and their support documents. 
6.4 
Calculated Outcomes 
The following are key endpoints derived from data captured at the sites via the EDC 
system.  Complete documentation of the calculations and data manipulation required to 
go from the CRF database to the analysis database are contained in the companion 
document - the study Analysis Programming Requirements (APR) for SDTM and ADaM. 
Endpoint 
Calculation 
Comment 


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Baseline value 
Value reported prior to study 
treatment, i.e., NanoDoce direct 
injection 
If multiple values collected 
prior to treatment initiation, 
non-missing value closest 
to the date/time of direct 
injection is considered 
baseline 
Change from 
Baseline 
Value collected at time point (Visit) – 
Baseline value 
 
Time in Trial 
(days) 
Study completion/withdrawal date – 
date of informed consent date + 1 day 
 
Time on 
Treatment 
(days) 
Date/End Time of last intravesical 
instillation – Date/Start Time of 
NanoDoce direct injection 
 
Treatment 
Emergent 
Adverse Event 
(TEAE) 
= no if onset date/time AE is before 
the date/time of NanoDoce direct 
injection, or after the End of 
Treatment visit, i.e. Month 6 for Group 
1 / Group 2 subset; Day 45 for Group 
2  
= yes otherwise 
According to conservative 
rule, all AEs that cannot be 
determined as started 
before NanoDoce injection 
or after EoT will be 
considered as TEAE 
Age (years) 
= Informed Consent Year – Birthdate 
Year,  if consent date was on or 
after birthday, 
= Informed Consent Year – 
Birthdate Year – 1, if consent date 
was before birthday 
 


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Recurrence 
Free Survival 
(RFS) Time 
(months) 
= ((Date of first recurrence or death – 
Date of NanoDoce direct injection + 1) 
/ 365.25) * 12, if the subject had 
recurrence or died during the study 
= ((Date of cystectomy or last alive 
date – Date of NanoDoce direct 
injection + 1) / 365.25) * 12, if the 
subject had no recurrence before 
cystectomy or last alive date 
Note:  
1) This RFS time will only 
be calculated for Group 1 
(NMIBC) subjects. 
2) Due to the small number 
of subjects in each cohort 
or treatment group, RFS 
time will not be analyzed 
using K-M analysis and 
log-rank test.  
Disease 
Progression at 
Day 45 
= Yes. if the subject had disease 
progression on/before Day 45 visit, 
which is End of Treatment visit of the 
Group 2 subjects 
= No, if the subjects had no disease 
progression at Day 45 visit.  
This variable is only 
calculated for MIBC 
subjects, including both 
Group 2 subset and other 
Group 2 subjects 
Overall 
Survival (OS) 
Time (months) 
= ((Date of death – Date of NanoDoce 
direct injection + 1) / 365.25) * 12, if 
the subject died during the study, 
 
Note: Due to the small 
number of subjects in each 
cohort or treatment group, 
OS time will not be 
analyzed using K-M 
analysis and log-rank test. 
Therefore, OS time for 
censored subject is not 
calculated.  
6.5 
Analysis Population 
All enrolled subjects who receive NanoDoce injection will be the analysis population for all 
outcome analyses.  


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6.6 
Interim Analysis/ Data Monitoring 
No interim analysis is planned for this trial. The safety data (e.g., Adverse Events, dose 
limiting toxicities, vital signs, laboratory values, etc.) will be reviewed on an ongoing basis 
throughout the study by the Data Safety Monitoring Board (DSMB), to evaluate the risk for 
the subjects and to make dosing recommendations.  
The trial statistician will provide safety report to DSMB for each cohort of the dose-finding 
phase after the first 3 subjects of the cohort complete the study. If additional 3 subjects 
are enrolled to the same dose level, the safety report will be provided again for all 6 
subjects of the cohort.  
6.7 
Analysis Methods 
All calculations and analyses will be performed using SAS version 9.4 or higher under the 
Windows Server 2012R2 operating system at McDougall Scientific Ltd. in Toronto, 
Canada.  Continuous data will be summarized via PROC MEANS - mean, standard 
deviation, median, range, and 95% CIs, while categorical data will be presented as counts 
and percentages (or proportions) via PROC FREQ for the descriptive displays.  
No statistical inference will be made for all outcomes. 
7 
RESULTS 
All enrolled and treated subjects will be the analysis population for all analyses. All data 
collected in EDC will be at a minimum listed.  
Because of the different disease types (i.e., NMIBC vs. MIBC) and different treatment 
schedules, all tables, listings, and graphs will be presented separately for Group 1, Group 
2 Subset, and Group 2.  
All outcomes will be summarized by cohort, i.e., dose level of direct injection, and visit, if 
applicable.  
All outcomes will also be summarized by treatment group, i.e., combination of direct 
injection dose and instillation dose (0.75/2.0 mg/mL, 0.75/3.0 mg/mL, 1.5/2.0 mg/mL, 
1.5/3.0 mg/mL …).  
All outcomes will also be summarized for the total treated subjects. 
All available data of screen failures will be provided in a separate listing. 


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7.1 
Study Subjects 
7.1.1 
Patient Disposition 
All enrolled and treated subjects will be accounted for. Number of subjects in the analysis 
population, study completion status, and time in trial will be summarized by cohort and by 
treatment group. 
All early discontinuations will be summarized by primary reason of discontinuation. 
7.1.2 
Demographics and Baseline Characteristics  
Demographic (age, sex, ethnicity, and race), baseline body measurements (height, 
weight, and calculated BMI), and vital signs (blood pressures, heart rate, and body 
temperature) will be summarized. 
7.1.3 
Medical History 
Medical history will be coded in MedDRA and summarized by System Organ Class (SOC) 
and Preferred Term (PT). 
7.1.4 
TURBT 
All TURBT information at Study Day 1, including date, start/end time of resection, number 
of resection sites, target lesion size, etc., will be presented in data listing. 
7.1.5 
NanoDoce Administration 
NanoDoce direct injection data at study Day 1, including dose level, injection date, 
start/end time, number of injections, total volume (in mL) and dose (in mg) injected, and 
bladder location of injection, will be listed. 
NanoDoce instillation data at study Day 1, induction period, and maintenance period, 
including dose level, instillation date, start/stop time, void time, instillation volume (in mL) 
and dose (in mg), will be listed. 
Time on treatment and total number of instillations will be summarized. 
7.2 
Primary Outcomes 
The primary endpoint will be safety and tolerability, as demonstrated by adverse events 
(AE), changes in laboratory assessments, physical examination findings, and vital signs.  
All primary outcomes will be descriptively summarized by cohort, by treatment group, and 
for the total treated subjects. No statistical inference will be made for primary endpoint.  


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7.2.1 
Adverse Events 
For this study, Treatment Emergent Adverse Events (TEAEs) are limited to AEs during 
the treatment period. That is, TEAEs are adverse events with onset date on/after the first 
study dose (injection), and on/before the End of Treatment visit (Month 6 for Group 
1/Group 2 subset; Day 45 for Group 2).  
The AEs of special interest will be flagged and tabulated. They are signs of systemic 
toxicity due to docetaxel exposure as well as local reactions; particularly from bladder 
injection. NanoDoce has never previously been injected in the bladder; subjects will be 
monitored for injection site pain and any reported event, in particular, during the first 36 
hours after the procedure. 
Summaries of AEs will be prepared by treatment group, and include: 
x 
Overview of all AEs - include the total number of TEAEs, serious TEAEs, death, 
and AEs leading to early discontinuation.  
x 
AEs by MedDRA System Organ Class (SOC) and Preferred Term (PT)  
x 
AEs by MedDRA SOC, PT, and relationship to NanoDoce treatment. 
x 
AEs by MedDRA SOC, PT, and severity. 
x 
SAEs by MedDRA System Organ Class (SOC) and Preferred Term (PT).  
x 
AEs with fatal outcome. 
x 
AEs leading to early discontinuation. 
x 
AEs of Special Interest 
x 
DLTs 
All these summaries will include the counts and frequencies of events, and of subjects 
who had events.  
All AEs will be listed by subject. Death, DLT, and other SAEs will be listed separately. 
7.2.2 
Laboratory Assessments 
Laboratory assessments, including assessments at each visit and change from baseline 
at post-baseline visits, will be summarized by visit and analyte.  
Each non-missing lab result’s normal/abnormal status (e.g. normal/low/high for 
quantitative results, and normal/abnormal for qualitative results) will be calculated based 
on the normal reference ranges provided by the lab. The status will be summarized using 
shift tables from baseline to each post-baseline time point. 
All lab data will be presented in by-subject data listing. Separate listings will be provided 
for subjects with abnormal lab values which are judged by the investigator to be clinically 
significant. 
Following lab tests are required for the study: 


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Chemistry: Sodium, potassium, chloride, carbon dioxide (CO2), calcium, phosphorus, 
glucose, blood urea nitrogen (BUN), creatinine, serum lipase, serum amylase, 
alkaline phosphatase (ALP), total bilirubin, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), lactate dehydrogenase (LDH), total protein, 
albumin, triglycerides, cholesterol, uric acid and calculated creatinine 
clearance. 
Hematology: Red blood cells (RBC), white blood cells (WBC) including complete 
differential, hemoglobin (Hgb), hematocrit (Hct), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), platelet (Plt) and reticulocyte count; 
Coagulation and Fibrinogen assay: Prothrombin time (PT), international normalized ratio 
(INR), activated partial thromboplastin time (aPTT), and fibrinogen; 
Urinalysis: Specific gravity, hydrogen ion concentration (pH), RBC, WBC, protein, and 
glucose. 
7.2.3 
Physical Examination 
All abnormal findings from the physical examination after study treatment will be recorded 
as AEs. The analysis of physical examination will be included in AE summaries. See 
section 7.2.1. 
7.2.4 
Vital Signs 
Vital Signs (blood pressure, heart rate, temperature, respiratory rate) will be summarized 
for each visit. 
Vital Signs’ change from baseline values will be summarized at all post-treatment visits. 
Unscheduled vital signs will only be presented in by-subject data listing.  
7.2.5 
12-Lead ECG 
12-Lead ECG assessed at Screening and End of Treatment visit will be descriptively 
summarized. 
7.3 
Secondary Outcomes 
7.3.1 
Plasma Docetaxel Concentration  
All numeric docetaxel concentration data above the Lower Limit of Quantitation (LLOQ), 
i.e. the detectable limit, will be tabulated by visit/time point using the arithmetic mean, 
standard deviation, coefficient of variation, median, and range. 
All docetaxel concentration data (individual subjects and mean of treatment group) will be 
visually presented in spaghetti plots by treatment group. 


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7.3.2 
Recurrence-Free Survival and Disease Progression 
Group 1 (NMIBC) subjects  
Each NMIBC subject’s Recurrence-Free Survival (RFS) time will be calculated based on 
the disease recurrence data and death information. The recurrence data is a composite of 
all cytology and tumor biopsy assessments. For subjects who had no recurrence before 
cystectomy or alive at last contact, i.e., censored subjects, their RFS time will be the time 
from initial treatment to the date of cystectomy or last alive date. 
RFS status (yes/no) at Visit 10 (1st maintenance instillation) and Visit 13 (End of Treatment 
visit), as well as RFS time will be summarized by cohort and for total Group1 subjects. 
Group 2 (MIBC) subjects  
Disease progression status at Day 45 will be summarized for MIBC subjects. Time to 
cystectomy, death, or last alive contact will be listed. 
7.3.3 
Overall Survival 
Overall survival (OS) time will be calculated for subjects who died during the study. Death 
date, overall survival time, and cause of death will be listed.  
The surviving (yes/no) at 6, 9, 12-month follow-ups will be summarized.   
7.3.4 
Cystoscopy, Cytology, and Biopsy 
Cystoscopy and cytology data are required at Visits 4, 10 and End of Treatment; ad-hoc 
cystoscopy, urine cytology, and ‘for-cause’ biopsy can be conducted at any time during 
the study as needed.  
Cytology categorical data, like types and results, will be descriptively summarized. 
All cystoscopy, cytology, and biopsy data collected in EDC will be listed.   
7.3.5 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
ECOG performance scale collected at screening, Day 1, and during study will be 
summarized by cohort and by treatment group. 
7.3.6 
Immunohistochemistry Data 
All immunohistochemistry data will be reported separately and inserted as an appendix or 
addendum to the Clinical Study Report.   
7.4 
Safety Outcomes 
All safety analyses will be presented as the primary outcome analysis. See section 7.2. 


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7.5 
Other Outcomes 
7.5.1 
Prior and Concomitant Medications 
A summary of all concomitant medications taken during the course of the study will be 
presented in tabular form by therapeutic drug class (ATC Level 2 code) and generic drug 
name (ATC Level 4 code) using the World Health Organization Drug Dictionary (WHODD).  
Prior medications, i.e., started and stopped before direct injection, will be summarized and 
listed separately. 
7.5.2 
Concomitant Procedures 
All concomitant procedures performed during the study will be listed.  
 
 
 


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Appendix A: ECOG Performance Scale 
 
Patient performance status will be graded according to the Eastern Cooperative 
Oncology Group (ECOG) scale* as described below.  
 
Grade ECOG PERFORMANCE STATUS DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5 
Dead 
 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982.