Conditions: Non-muscle Invasive Bladder Cancer (NMIBC)
Keywords: BCG-unresponsive
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
This study, BC-819-18-204, is a Phase 2, open-label, monotherapy, single-arm, multicenter clinical trial of BC-819 (inodiftagene vixteplasmid) in patients with NMIBC adequately treated with Bacillus Calmette-Guerin (BCG) whose disease is BCG unresponsive according to the US Food and Drug Administration (FDA) guidance.

Detailed description:
BC-819 (inodiftagene vixteplasmid) is a recombinant DNA plasmid that directs the expression of a potent toxin specifically in malignant cells but not in normal tissue. It has been designed to exploit the established biology of the H19 gene, which is upregulated and expressed at high levels only in malignant cells, to produce bacterial diphtheria toxin only in bladder cancer tissue. BC-819 is administered directly into the bladder to enable maximal topical exposure to target bladder cancer cells.

Arms:
arm 1: inodiftagene vixteplasmid

Interventions: intervention 1: inodiftagene vixteplasmid
Intervention descriptions: intervention 1: BC-819 at 20 mg/50 mL, instilled intravesically into the bladder, with a retention time of at least 30 minutes (up to 2 hours).

Induction Phase (weekly treatments): 10 weekly treatments; Maintenance Phase: treatment every 3 weeks for up to 84 additional weeks

Protocol document:
Prot_000.pdf: 
Protocol Number: BC-819-18-204 (version 1.4) 
Anchiano Therapeutics Israel Ltd. 
 
Date of protocol: 24 Sep 2018 
 
Confidential 
Page 1 
CLINICAL STUDY PROTOCOL 
Protocol Title: A Phase 2 Study of BC-819 in Patients with Non-Muscle 
Invasive Bladder Cancer Whose Disease is Unresponsive to Bacillus 
Calmette-Guerin  
Protocol Number: 
BC-819-18-204 (version 1.4) 
Study Product: 
BC-819 (inodiftagene vixteplasmid) 
Indication: 
Non-muscle invasive bladder cancer in patients whose 
disease is unresponsive to bacillus Calmette-Guerin  
Phase: 
2 
EudraCT Number: 
2017-000655-67 
IND Number: 
13588 
Study Institutions/Locations: 
Multicenter, multinational study 
Name and Address of 
Sponsor: 
Anchiano Therapeutics Israel Ltd 
1/3 High Tech Village 
Givat Ram, Jerusalem, Israel 
PO Box 39264 913902, Israel 
Good Clinical Practice (GCP) 
Statement: 
This study will be performed in compliance with GCP, 
including the archiving of essential documents. 
The information in this document is confidential and is proprietary to Anchiano Therapeutics 
Israel Ltd.  It is understood that information in this document shall not be disclosed to any third 
party, in any form, without prior written consent of Anchiano Therapeutics Israel Ltd. 
 
 


Protocol Number: BC-819-18-204 (version 1.4) 
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Date of protocol: 24 Sep 2018 
 
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DOCUMENT APPROVAL 
This study will be conducted in compliance with the protocol, GCP, and all applicable 
regulatory requirements. 
 
 
SPONSOR REPRESENTATIVES: 
 
___________________________________________ 
 
_______________________ 
Signature: 
 
 
 
 
 
 
 
Date 
Print Name: __________________________________ 
Title: _______________________________________ 
 
 
 
___________________________________________ 
 
_______________________ 
Signature: 
 
 
 
 
 
 
 
Date 
Print Name: __________________________________ 
Title: _______________________________________ 
 


Protocol Number: BC-819-18-204 (version 1.4) 
Anchiano Therapeutics Israel Ltd. 
 
Date of protocol: 24 Sep 2018 
 
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1. 
SYNOPSIS 
TITLE: A Phase 2 Study of BC-819 in Patients with Non-Muscle Invasive Bladder Cancer Whose 
Disease is Unresponsive to Bacillus Calmette-Guerin 
INVESTIGATIONAL PRODUCT: Recombinant DNA plasmid complexed with polyethylenimine, 
hereafter referred to as BC-819 or inodiftagene vixteplasmid. 
INDICATION: Non-muscle invasive bladder cancer (NMIBC) in patients whose disease is unresponsive 
to bacillus Calmette-Guerin (BCG) 
PHASE OF DEVELOPMENT: 2 
INVESTIGATIONAL SITES/LOCATIONS: Multicenter, multinational (United States [US] and 
Non-US sites)  
OBJECTIVES:  
Primary: 
The primary objective is to determine, for the patients with baseline CIS: 
• 
The proportion that achieves a complete response after treatment with inodiftagene vixteplasmid 
Secondary: 
The secondary objectives are to determine the: 
• 
Proportion of patients with absence of high-grade recurrent or persistent disease at 48 weeks 
(overall population and subgroup of patients with CIS) 
• 
Proportion of patients with absence of high-grade recurrent or persistent disease at 12, 24, 36, 72, 
and 96 weeks (overall population and subgroup of patients with CIS) 
• 
Time to recurrence (Kaplan-Meier plot) 
• 
Proportion of patients who are progression-free at 48, 72, and 96 weeks 
• 
Overall survival of patients enrolled in the study at 48, 72, and 96 weeks 
• 
Quality of life in patients treated with inodiftagene vixteplasmid 
• 
Assessment of safety 
STUDY DESIGN: 
This study, BC-819-18-204 (referred to as Study 204), is a Phase 2, open-label, monotherapy, single-arm, 
multicenter clinical trial of BC-819 (inodiftagene vixteplasmid) in patients with NMIBC adequately 
treated with BCG whose disease is BCG-unresponsive according to the US Food and Drug Administration 
(FDA) guidance.  Patients with BCG-unresponsive disease have NMIBC that is unlikely to benefit from 
and should not be treated with further intravesical BCG.  
Patients are to have recurred or progressed after adequate treatment, had BCG-unresponsive disease, had a 
transurethral resection (TUR), and then had all papillary disease completely resected and obvious CIS 
disease fulgurated when indicated.  Patients must have 1 or more of the following: completely resected 
high-grade T1 disease, CIS disease, or completely resected high-grade Ta disease.  There is no 
intravesical or medical standard of care for this patient population, and the usual course is radical 
cystectomy.    


Protocol Number: BC-819-18-204 (version 1.4) 
Anchiano Therapeutics Israel Ltd. 
 
Date of protocol: 24 Sep 2018 
 
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A total of 140 patients who meet study entry criteria will be enrolled and treated.  The first 35 patients 
enrolled and treated must have CIS (with or without papillary disease).  After these 35 patients are treated 
and 10 complete responders are documented, the enrollment will expand to also allow patients with 
papillary disease only who meet inclusion and exclusion criteria.  It is estimate that a total of 
approximately 70 to 100 patients with CIS will be treated.   
All enrolled patients will enter the 10-week induction phase and begin treatment with BC-819.  Treatment 
should begin within 7 days of enrollment and ≤42 days from the last TUR or biopsy.  During the induction 
phase, patients will receive an intravesical instillation of BC-819 at a dose of 20 mg/50 mL aqueous 
solution once per week for 10 weeks according to the induction phase treatment schedule (see Table 12.1).   
Upon completion of the induction phase, patients will continue with maintenance therapy of BC-819 
every 3 weeks beginning at Week 12 (Visit 11) and continuing for the next 84 additional weeks until the 
end of the study, defined as completion of the 96-week visit (Visit 39).   
During the study, patients will undergo repeat direct visualization (ie, cystoscopy ± biopsy and cytology) 
and repeat TUR (as needed for cause) every 12 weeks during the first and second year.  Patients with 
persistent CIS which does not resolve by the 12-week assessment, or at subsequent 12-week assessments, 
or who have recurrence or new evidence of CIS or high-grade papillary disease at any time will be 
discontinued and classified as nonresponders and recurrences in the primary and secondary endpoint 
analyses.  Patients benefiting from treatment, with no documented high-grade recurrence or progression, 
will continue to receive maintenance therapy every 3 weeks.  Appearance or persistence of lower grade 
tumors will not be considered as recurrence for the primary and secondary endpoint analyses, and patients 
with only low-grade tumors should continue treatment after resection and histological confirmation.   
NUMBER OF PATIENTS (PLANNED):  It is planned to enroll and treat 140 patients (N=140), of 
which 70 to 100 are estimated to have CIS (with or without papillary disease).  Assuming at least 
70 patients with CIS, this sample size will provide over 95% power to detect a difference between CR rate 
in CIS patients of 20% and an alternative hypothesis proportion of 40% using an exact binomial test with 
a nominal 0.05 two-sided significance level.  If 100 CIS patients are enrolled, the power will be 
approximately 92% to detect a difference from 20% assuming an alternative hypothesis proportion of 
35%.  The power is higher to detect a difference from CR rates lower than 20%. 
 


Protocol Number: BC-819-18-204 (version 1.4) 
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Date of protocol: 24 Sep 2018 
 
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DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION AND EXCLUSION:   
Eligible patients must meet the following inclusion criteria: 
1. Male or female patients ≥18 years of age at the time of consent 
2. Patient must have been adequately treated with BCG defined as at least one of the following 
(FDA 2018):  
a. 
At least five of six doses of an initial induction course plus at least two of three doses of 
maintenance therapy 
b. At least five of six doses of an initial induction course plus at least two of six doses of a 
second induction course 
c. 
A single course of induction BCG can qualify if the patient has T1 high-grade disease at 
first evaluation (see 3c) 
3. Patient must be BCG-unresponsive defined as at least one of the following (FDA 2018): 
a. 
Persistent or recurrent CIS alone or with recurrent Ta/T1 disease within 12 months of 
completion of adequate BCG therapy.  An assessment within 15 months can also qualify 
when no assessment was done 12 months after completion of adequate BCG therapy 
b. Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG 
therapy.  An assessment within 9 months can also qualify when no assessment was done 
6 months after completion of adequate BCG therapy 
c. 
T1 high-grade disease at the first evaluation following a single course of induction BCG 
qualifies (Lerner et al. 2015, Steinberg et al. 2016) 
4. Patient must have, at study entry, NMIBC indicated by 1 or more of the following: 
a. 
Ta or T1 high-grade disease 
i. No more than 42 days may elapse between the start of protocol therapy and 
complete resection of Ta/T1 papillary disease qualifying the patient for the 
study 
b. CIS disease 
i. Obvious areas of CIS should be fulgurated prior to start of therapy when 
indicated 
5. Patient must have no known evidence of concomitant upper tract urothelial carcinoma or 
urothelial carcinoma within the prostatic urethra within 6 months of enrollment 
6. Patient must have an Eastern Cooperative Oncology Group performance status ≤2 
7. Patient must have adequate hematologic function, as demonstrated by the following: 
a. 
Hemoglobin level ≥10 g/dL 
b. Absolute neutrophil count ≥1.5 x 109/L 
c. 
Platelet count ≥100 x 109/L 
8. Patient must have adequate liver and renal function as demonstrated by the following: 
a. 
Aspartate aminotransferase and alanine aminotransferase each ≤3.0 x upper limit of 
normal 
b. Total bilirubin ≤1.5 x upper limit of normal, unless prior documentation of Gilbert’s 
syndrome in which case, 3.0 mg/dL is allowed 
c. 
Serum creatinine ≤1.5 x upper limit of normal or measured or calculated creatinine 
clearance ≥30 mL/min  
9. Female patients of childbearing potential must use maximally effective birth control during the 
period of therapy (ie, a combination of 2 regulatory approved methods), must be willing to use 
contraception for 1 month after the last study drug infusion, and must have a negative urine or 
serum pregnancy test result upon entry into the study.  Otherwise, female patients must be 
postmenopausal (no menstrual period for a minimum of 12 months) or surgically sterile   


Protocol Number: BC-819-18-204 (version 1.4) 
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Date of protocol: 24 Sep 2018 
 
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10. Male patients who are sexually active must be willing to use a double-barrier contraceptive 
method upon study enrollment, during the course of the study, and for 1 month after the last 
study drug infusion 
11. Patient must be able to understand and sign an informed consent form  
12. Patient must be able to comply with protocol requirements, including attendance at required 
clinic visits 
The presence of any of the following excludes a patient from study enrollment: 
1. Patient has current or previous evidence of muscle invasive (muscularis propria) or metastatic 
bladder cancer disease  
2. Patient has received investigational therapy for NMIBC 
3. Patient has received any therapy for NMIBC within 10 weeks before the start of study treatment 
other than surgical resection, 1 dose of chemotherapy, and previous BCG 
4. Patient is intolerant to previous BCG treatment in the absence of meeting other criteria for 
BCG unresponsiveness and adequate BCG therapy  
5. Patient has received external beam radiation therapy for bladder cancer at any time or for any 
other condition  
6. Patient has an active infection, including urinary tract infection (viral, bacterial, or fungal) and 
cystitis 
7. Patient has urinary tract signs or symptoms that preclude retention of drug in the bladder; this 
does not include anticholinergic drugs  
8. Patient is known have tested positive for human immunodeficiency virus (HIV).  No HIV testing 
is required if patient is not known to have tested positive 
9. Patient is female and is pregnant or breastfeeding 
10. Patient has any medical, psychological, or social condition or situation that may, in the 
investigator’s opinion, make it difficult for the patient to tolerate study medication or comply 
with study procedures and other requirements.  This includes but is not limited to active 
infections, poorly controlled diabetes, uncontrolled cardiac arrhythmia, angina pectoris, or 
hypertension 
11. Patient has a known presence or history of malignancy of other organ system within the 5 years 
before study start, with the exception of non-melanoma skin cancer (eg, basal cell carcinoma or 
squamous cell carcinoma of the skin); very low or low-risk prostate cancer (by National 
Comprehensive Cancer Network guidelines) defined as prostate-specific antigen <10 ng/dL, 
Gleason score ≤6, and clinical stage T1c; or patients who have been disease-free for at least 
2 years following stage 1 or 2 cancer 
12. Patient is on immunosuppressive therapy or has had a transplant within 12 months before study 
start, except for chronic use of corticosteroids (eg, rheumatoid arthritis, asthma, chronic 
obstructive pulmonary disease, or any other similarly chronic use of steroids) 
13. Patient has any other significant disease that, in the opinion of the investigator, would prevent 
study entry 
 
TEST PRODUCT(S), DOSE AND MODE OF ADMINISTRATION:  BC-819 at 20 mg/50 mL, 
instilled intravesically into the bladder, with a retention time of at least 30 minutes (up to 2 hours) 
DURATION OF STUDY:  approximately 15 months of enrollment and 96 weeks of treatment 
• 
Induction Phase (weekly treatments): 12 weeks; 10 weekly treatments followed by 2 weeks for 
initial assessment of primary endpoint of complete response in CIS patients 


Protocol Number: BC-819-18-204 (version 1.4) 
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Date of protocol: 24 Sep 2018 
 
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Maintenance Phase (treatment every 3 weeks):  84 additional weeks; assessment of EFS endpoint at 
48 weeks (36 weeks after initiation of maintenance therapy); completion of therapy at 96 weeks 
DISCONTINUATION FROM TREATMENT:   
Reasons for permanent discontinuation include the following: 
1. In patients with CIS at baseline, failure to clear CIS lesions by Week 12; however, patients who 
clear CIS lesions but have low-grade disease should continue treatment.  Patients with CIS 
lesions that fail to clear may be followed by cystoscopy until they have a cystectomy or start an 
alternative treatment, but will be considered non-responders in the primary efficacy analysis  
2. Recurrence or appearance of high-grade papillary lesions at the Week 12 cystoscopy or later or 
of CIS lesions after clearance.  Only patients who meet the definition of recurrence should be 
discontinued.  Patients with persistence or appearance of lower grade disease should not 
be discontinued 
3. Unacceptable toxicity, defined as a persistent Grade 3 adverse event (AE) or higher, as assessed 
by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0, despite dosing delay and/or symptomatic treatment (according to the AE 
management guidelines in Section 9.5) 
4. Withdrawal of consent 
 
Any patient without tumor in the bladder but presence of tumor in the upper urinary tract will not be 
classified as a failure in the primary analyses and will continue study participation. 
PRIMARY EFFICACY ENDPOINT: 
The primary efficacy endpoint is, in patients with CIS at baseline, the:  
• 
Proportion that achieves a complete response anytime on or after 12 weeks and within the first 
48 weeks  
Complete response in patients with CIS is defined as at least one of the following: 
• 
Negative cystoscopy and negative (including atypical) urine cytology 
• 
Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative cytology 
• 
Negative cystoscopy with malignant urine cytology if cancer is found in the upper tract or prostatic 
urethra and random bladder biopsies are negative 
The complete response in patients with CIS for this endpoint must be documented on or after the Week 12 
response assessment and on or prior to the Week 48 assessment.  Duration of complete response in CIS 
patients will be calculated from the documented onset of the complete response to the assessment where 
the patient no longer meets the definition of complete response.  More generally, recurrence is defined as 
the reappearance or persistence of high-grade disease or new high-grade disease including CIS.  
Recurrence must be biopsy proven.  Persistence, appearance, or presence of lower grade disease will not 
be considered recurrence. 
  
SECONDARY EFFICACY ENDPOINTS: 
The secondary endpoints include the following: 
• 
The incidence of EFS at 48 weeks, where EFS is defined as high-grade recurrence-free survival 
(overall population and subgroup of patients with CIS) 
• 
The incidence of EFS at 12, 24, 36, 72, and 96 weeks, where EFS is defined as high-grade 
recurrence-free survival (overall population and subgroup of patients with CIS) 
• 
Time to recurrence; recurrence is defined as an EFS event  
• 
The incidence of progression-free survival at 48, 72, and 96 weeks as well as time to progression 
estimated using Kaplan-Meir methods.  Progression is defined as the development of T2 or 


Protocol Number: BC-819-18-204 (version 1.4) 
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Date of protocol: 24 Sep 2018 
 
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Page 8 
greater disease.  Sensitivity analyses will also be performed and will include any of the following 
as progressions: 
o 
An increase in stage from Ta or CIS to T1, or  
o 
Development of T2 or greater, or  
o 
Lymph node disease, or  
o 
Distant metastasis  
• 
Overall survival of patients enrolled in the study at 48, 72, and 96 weeks and survival time 
estimated using Kaplan-Meier methods 
• 
Changes in quality of life over time, as measured by the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; a general questionnaire 
for cancer) and the Non-Muscle Invasive Bladder Cancer Questionnaire (QLQ-NMIBC24; a 
specific questionnaire for NMIBC disease) 
 
SAFETY ENDPOINT: 
The safety endpoint is occurrence of AEs according to CTCAE version 5.0, regardless of relationship to 
study medication. 
STATISTICAL ANALYSIS: 
Analyses will generally be performed for the entire patient population, subgroups of patients with 
papillary lesions only, and patients with CIS (with or without papillary lesions).  Determination of success 
for the treatment will be based on the full analysis set population of all treated patients. The primary 
endpoint will be analysed using a two-sided 95% binomial exact CI (Clopper-Pearson) for the rate of 
patients with baseline CIS who have a complete response.     
Duration of response in CIS patients who have a complete response will be calculated using Kaplan-Meier 
methods starting from the documented onset of the complete response to the assessment where the patient 
no longer meets the definition of complete response..   
In addition to time point analyses of rates of freedom from recurrence, Kaplan-Meier plots of 
recurrence-free survival will be calculated for all patients.  Kaplan-Meier methods will also be used to 
estimate progression-free survival and overall survival rates at 48, 72, and 96 weeks. 
The first 35 patients enrolled are to have CIS (with or without papillary disease).  An interim futility 
analysis will be performed on these patients and if 9 or fewer of these patients have complete responses 
the study may be discontinued.  Once the first 35 patients with CIS are enrolled and 10 or more complete 
responses are documented, enrollment may continue with the full study population (including patients 
with high-grade papillary disease without CIS who meet inclusion and exclusion criteria). 
 
 
 


Protocol Number: BC-819-18-204 (version 1.4) 
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Date of protocol: 24 Sep 2018 
 
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2. 
TABLE OF CONTENTS 
1. 
SYNOPSIS .............................................................................................................................. 3 
2. 
TABLE OF CONTENTS ........................................................................................................ 9 
3. 
TABLES ............................................................................................................................... 12 
4. 
LIST OF ABBREVIATIONS ............................................................................................... 13 
5. 
GLOSSARY OF TERMS ..................................................................................................... 15 
6. 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY REQUIREMENTS ...... 16 
 
Institutional Review Board (IRB) ................................................................................. 16 
 
Ethical Conduct of the Study ........................................................................................ 16 
 
Patient Information and Consent .................................................................................. 16 
 
Protocol Revisions and/or Deviations ........................................................................... 16 
 
Patient Insurance ........................................................................................................... 17 
 
Informing the Referring Physician................................................................................ 17 
7. 
INTRODUCTION ................................................................................................................ 18 
 
Bladder Cancer.............................................................................................................. 18 
7.1.1 Staging/Grading ........................................................................................................ 18 
7.1.2 Bacillus Calmette-Guerin‒Unresponsive Patients .................................................... 19 
 
BC-819 Background ..................................................................................................... 20 
 
BC-819:  Clinical Studies in Patients With Bladder Cancer......................................... 21 
7.3.1 Phase 1 Study ............................................................................................................ 22 
7.3.2 Phase 2 Monotherapy Study ..................................................................................... 23 
 
Phase 2 Combination Study .......................................................................................... 24 
 
Rationale for Study ....................................................................................................... 24 
8. 
STUDY OBJECTIVES ......................................................................................................... 26 
 
Primary Objectives........................................................................................................ 26 
 
Secondary Objectives.................................................................................................... 26 
9. 
INVESTIGATIONAL PLAN ............................................................................................... 27 
 
Overall Study Design and Plan—Description .............................................................. 27 
 
Discussion of Study Design and Choice of Control Group(s) ...................................... 27 
 
Selection of Study Population ....................................................................................... 28 
9.3.1 Inclusion Criteria ...................................................................................................... 28 
9.3.2 Exclusion Criteria ..................................................................................................... 29 


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Study Treatment Plan .................................................................................................... 30 
9.4.1 Enrollment Period ..................................................................................................... 30 
9.4.2 Induction Phase ......................................................................................................... 32 
9.4.3 Maintenance Treatment ............................................................................................ 32 
 
Dosing Delays ............................................................................................................... 34 
 
Discontinuation of Therapy .......................................................................................... 35 
10. 
STUDY PRODUCT.......................................................................................................... 36 
 
Study Medication Supply .............................................................................................. 36 
 
Description of Study Product ........................................................................................ 36 
 
Packaging and Labeling ................................................................................................ 36 
 
Conditions for Storage and Use .................................................................................... 36 
10.5 
Method of Assigning Patients to Treatment Groups..................................................... 36 
10.6 
A Dispensing, Compliance and Accountability ............................................................ 36 
10.7 
Concomitant Therapy.................................................................................................... 36 
11. 
EFFICACY AND SAFETY ASSESSMENTS ................................................................. 37 
11.1 
Primary Efficacy Variable ............................................................................................ 37 
11.2 
Secondary Efficacy Variables ....................................................................................... 37 
11.3 
Safety Variables ............................................................................................................ 38 
11.3.1 
Clinical Laboratory ............................................................................................... 38 
11.3.2 
Adverse Events ..................................................................................................... 38 
12. 
STUDY PROCEDURES AND FLOWCHARTS ............................................................ 43 
12.1 
Description of Study Procedures .................................................................................. 48 
13. 
STATISTICAL METHODS PLANNED AND SAMPLE SIZE ..................................... 51 
13.1 
Determination of Sample Size ...................................................................................... 51 
13.2 
Patient Populations........................................................................................................ 51 
13.3 
Subject Disposition ....................................................................................................... 51 
13.4 
Demographics and Baseline Characteristics ................................................................. 52 
13.5 
Efficacy Analysis .......................................................................................................... 52 
13.5.1 
Primary Efficacy Analysis .................................................................................... 52 
13.5.2 
Interim Analyses ................................................................................................... 52 
13.5.3 
Secondary Efficacy Analyses ............................................................................... 53 
13.5.4 
Handling of Missing Data ..................................................................................... 54 


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13.6 
Safety Analysis ............................................................................................................. 54 
13.6.1 
Adverse Events ..................................................................................................... 54 
13.6.2 
Clinical Laboratory ............................................................................................... 55 
14. 
DATA QUALITY ............................................................................................................. 56 
14.1 
Source Data and Records .............................................................................................. 56 
14.2 
Electronic Data Capture ................................................................................................ 56 
14.3 
Data Management ......................................................................................................... 56 
14.4 
Study Master File .......................................................................................................... 57 
14.5 
Record Retention .......................................................................................................... 57 
14.6 
Confidentiality of Patient Data ..................................................................................... 57 
14.7 
Monitoring Plan ............................................................................................................ 57 
14.8 
Site Visits ...................................................................................................................... 57 
14.9 
Investigational Medicinal Product ................................................................................ 57 
14.10 Laboratory Samples and Analysis ................................................................................ 58 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................ 59 
15.1 
Audits and Inspections .................................................................................................. 59 
15.2 
Laboratory Quality Standards ....................................................................................... 59 
16. 
REPORTING AND PUBLICATION ............................................................................... 60 
16.1 
Confidentiality of Study Data ....................................................................................... 60 
16.2 
Publication Policy ......................................................................................................... 60 
16.3 
Study Registration ......................................................................................................... 60 
17. 
REFERENCES ................................................................................................................. 61 
 
 
 
 


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3. 
TABLES 
Table 9.1. TNM Staging Classifications .................................................................................... 31 
Table 11.1 
Contact Research Organization Contact Information ........................................... 42 
Table 12.1 
Induction Phase ..................................................................................................... 44 
Table 12.2 
Maintenance Treatment Through Visit 23 (Week 48) .......................................... 45 
Table 12.3 
Maintenance Treatment Through Visit 39 (Week 96) .......................................... 47 
Table 12.4 
Eastern Cooperative Oncology Group Performance Status:  Scored 0 (Normal 
Function) through 5 (Dead) .......................................................................................................... 49 
Table 13.1 
Urinary Tract‒Related Adverse Events ................................................................ 55 
 


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Date of protocol: 24 Sep 2018 
 
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4. 
LIST OF ABBREVIATIONS  
AE 
adverse event 
AUA 
American Urological Association 
BCG 
bacillus Calmette-Guerin 
CIS 
carcinoma in situ 
CR 
complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DM 
data manager 
DS 
drug substance 
DTA 
diphtheria toxin A 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EFS 
event-free survival 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire 
EOS 
end of study 
FAS 
full analysis set 
FDA 
US Food and Drug Administration 
GCP 
 
good clinical practice 
HIV 
human immunodeficiency virus 
ICF 
informed consent form  
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
ITT 
intent to treat 


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Date of protocol: 24 Sep 2018 
 
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MedDRA 
Medical Dictionary for Regulatory Activities 
NMIBC 
non-muscle invasive bladder cancer 
PEI 
polyethylenimine 
PFS 
progression-free survival 
PT 
preferred term 
QLQ-NMIBC24 
Non-Muscle Invasive Bladder Cancer Questionnaire 
re-TUR 
repeat transurethral resection 
SAE 
serious adverse event 
SOC 
system organ class  
SOP 
standard operating procedure 
SUSAR 
serious unexpected suspected adverse reaction 
TEAE 
treatment-emergent adverse event 
TUR 
transurethral resection 
US 
United States 
WBC 
white blood cell 
WHO 
World Health Organization 


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5. 
GLOSSARY OF TERMS 
Screened patient:  Patient first identified as being possibly eligible for the study.  Standard of 
care diagnostic, laboratory tests, and clinical assessment may be part of the data set used to 
determine patient eligibility. 
Eligible patient:  A patient meeting inclusion/exclusion criteria and eligible to be treated. 
Screen failure:  A patient who signed the informed consent form but was found to be ineligible 
to receive study drug.  
Treated patient:  Any patient who was administered study drug.  


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6. 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY REQUIREMENTS 
6.1 
Institutional Review Board (IRB) 
The study protocol and any amendments will be reviewed by an institutional review board (IRB). 
The IRB will review the informed consent form (ICF), any updates to the ICF, and any written 
materials provided to patients. A list of all IRBs and contact information will be included in the 
final clinical study report. 
6.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their origins in 
the 2013 revision of the Declaration of Helsinki by the World Medical Association, in 
compliance with the approved protocol, Good Clinical Practice (GCP), and all applicable 
regulatory requirements. 
6.3 
Patient Information and Consent 
The investigator will obtain a written (signed and dated by the patient) ICF from every patient 
eligible to participate in this study.  Obtaining an ICF involves providing the participant adequate 
information concerning the study, providing adequate opportunity for the participant to consider 
all options, responding to the participant’s questions, ensuring that the participant has 
comprehended this information, obtaining the participant’s voluntary agreement to participate, 
and continuing to provide information as the participant or situation requires.  To be effective, 
the process should provide ample opportunity for the investigator and the eligible patient to 
exchange information and ask questions. 
The investigator will also explain that eligible patients can decide to refuse to participate in this 
study or to withdraw from the study at any time and for any reason, without any consequences to 
his/her subsequent. 
The patient will receive a copy of the patient information and the signed ICF.  
The patient will be informed of any information that becomes available during the course of the 
study that may be relevant to his/her willingness to continue participation in the study. 
Eligible patients participating in this study will be informed that a monitor or a health authority 
inspector, in accordance with applicable regulatory requirements, may review the portions of 
patient source records and source data related to the study. Data protection and confidentiality 
will be handled in compliance with local laws. 
6.4 
Protocol Revisions and/or Deviations 
Changes to the protocol may be made only by the sponsor.  Approval for amendments must be 
obtained before any such changes can be implemented, except for changes necessary to eliminate 
an immediate safety concern to study patients, or for changes that involve only logistical or 
administrative aspects of the study.  No approval will be required for notifications.  
Protocol modifications made to the IRB/independent ethics committee (IEC)‒approved protocol 
or protocol amendment made for any reason by the investigator will constitute a protocol 
deviation, whether or not it is medically indicated.   


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6.5 
Patient Insurance 
The sponsor will maintain an insurance policy for the total duration of the study covering the 
patients and investigators with respect to the risks involved in conducting this study according to 
this protocol. The insurance policy will be filed in the investigator’s file or can be made available 
to the investigator and to the IRB/IEC upon request. 
6.6 
Informing the Referring Physician 
The investigator will inform the patient’s primary care physician of his/her participation in the 
study by sending a letter to the physician. 
 
 


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7. 
INTRODUCTION 
7.1 
Bladder Cancer 
Bladder cancer is a common illness, the ninth most common cancer worldwide and the fourth 
most common cancer in men in the United States.  An estimated 79,030 new cases of bladder 
cancer are expected to occur in the United States in 2017.  Bladder cancer incidence is about 
4 times higher in men than in women and almost 2 times higher in Caucasian men than in 
African-American men (American Cancer Society 2016).   
As most cases are detected early, the mortality rate for bladder cancer is only about 20% of its 
incidence, and its prevalence rate is high relative to its incidence rate.  Death rates for urinary 
bladder cancer have been stable in men since 1987 and decreasing in women by 0.4% per year 
since 1986.  An estimated 16,870 deaths from bladder cancer will occur in 2017.   
Most bladder cancers are transitional cell carcinomas, and most are superficial (ie, do not 
penetrate the muscularis layer), hence the term non-muscle invasive bladder cancer (NMIBC).  
The estimated proportion of patients with bladder cancer that is non-muscle invasive in the US is 
70% to 80% (Lamm 2002; Madeb et al. 2009; Shelley et al. 2010).  Of these new NMIBC cases, 
approximately 70% are Ta (confined to bladder epithelium), 20% are T1 lesions (invasion of 
lamina propria), and 10% are Tis disease (carcinoma in situ [CIS] lesions).  As much as 80% of 
patients with Ta disease can be expected to experience disease recurrence, and up to 45% of 
patients with T1 or CIS lesions will experience disease progression without treatment (van Rhijn 
et al. 2009). 
7.1.1 
Staging/Grading 
Prognosis and treatment of bladder cancer depends on the tumor stage (depth of penetration into 
or through bladder wall combined with nodal and metastatic status) and other parameters, 
including prior recurrences, number and size of tumors identified, tumor grade, and presence or 
absence of CIS lesions (Sylvester et al. 2006).  For definitions of staging and grading, see Table 
9.1.  NMIBC itself does not lead to mortality. However, if the tumor progresses and becomes 
invasive resulting in local progression or local or distant metastases, mortality increases 
considerably (Stein et al. 2001).  In addition, treatment of invasive bladder cancer requires 
radical cystectomy and/or adjuvant chemotherapy with significant increase in morbidity. 
The primary treatment approach to NMIBC is surgical therapy of resectable disease coupled with 
adjuvant therapy.  Intravesical bacillus Calmette-Guerin (BCG) instillation has been the mainstay 
of treatment of intermediate- and high-risk NMIBC for several decades (Lamm 2002).  It is used 
as an adjuvant after transurethral resection (TUR) of papillary carcinomas and for the treatment 
of CIS lesions.  BCG has been shown to decrease progression as well as recurrence (Sylvester et 
al. 2002).  Several chemotherapeutic agents, including mitomycin C, have also shown efficacy in 
certain groups of patients with NMIBC (Shelley et al. 2010).  However, recurrence is the norm, 
with approximately 60% to 70% of patients experiencing recurrences after initial treatment and 
25% progressing to invasive disease (Morgan et al. 2011).  Hence, there is an established unmet 
medical need and new treatment agents are needed. 


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7.1.2 
Bacillus Calmette-Guerin‒Unresponsive Patients  
While treatment with BCG has markedly reduced recurrence after TUR of papillary tumors and 
resolves CIS lesions in some patients, about 30% to 40% of patients eventually fail treatment 
with BCG (Zlotta et al. 2009).  A subgroup of patients who fail BCG are considered “BCG-
unresponsive.” BCG-unresponsive patients with high-grade NMIBC must have been adequately 
treated with BCG. These patients include those who did not respond to BCG treatment and have 
persistent or recurrent CIS within 12 months after BCG was initiated, those with recurrent high-
grade NMIBC within 6 months of their last intravesical treatment with BCG, or those with high-
grade T1 disease at the first evaluation following induction (FDA 2018). Adequate treatment 
generally requires either at least 5 of 6 induction doses and at least 2 of 3 maintenance doses or 
at least 5 of 6 induction doses plus at least 2 of 6 doses of a second induction course. No 
intravesical or systemic agents are currently known to be effective for treatment of these patients 
so as to be considered standard treatment.  Data from studies of gemcitabine in patients whose 
disease has failed BCG (Skinner et al. 2013; DiLorenzo et al. 2010) demonstrate a 2-year 
disease-free survival rate of approximately 20%, and data from studies of docetaxel (Laudano et 
al. 2010) are similar.  Therefore, the currently recommended therapy for BCG-unresponsive 
NMIBC is cystectomy, either partial or radical (Yates et al. 2012).  However, because of 
concomitant conditions, many patients are not candidates for major surgery such as cystectomy.  
These patients must currently rely on options with minimal effectiveness in this situation (eg, 
instillations of chemotherapeutic agents or repeat TURs [re-TURs]). 
The US Food and Drug Administration (FDA) and the American Urological Association (AUA) 
convened a workshop to address the development of new therapies for patients with NMIBC 
(Jarow et al. 2014).  The workshop participants addressed the BCG-unresponsive patient 
population.  They agreed that there was no consensus standard-of-care approach for these 
patients apart from cystectomy and that no therapy could be agreed upon to serve as a control for 
randomized clinical studies in this setting.  The participants recommended that single-arm 
Phase 2 studies could support regulatory approval for these patients.  Moreover, for patients with 
CIS lesions, it was recommended that a study achieving at least a 30% recurrence-free survival at 
18 to 24 months, with a sample size whose CI excluded a lower boundary of 20%, would be 
appropriate.  This recommendation has provided, in essence, a road map to drug development 
and approval in this setting. 
A more detailed FDA draft guidance document was published in November 2016 entitled BCG-
Unresponsive Non-Muscle Invasive Bladder Cancer:  Developing Drugs and Biologics for 
Treatment: Guidance for Industry, which re-states and extends the recommendations of the 
FDA/AUA workshop.  The FDA recommends that early stage development of agents for 
NMIBC should involve demonstration of activity against extant disease, for example, in marker 
lesion studies.  The guidance defines BCG-unresponsive patients as those with persistent high-
grade NMIBC who have been adequately treated with BCG who did not respond to BCG 
treatment and have a new (if previously treated for a low-grade NMIBC) or persistent high-grade 
recurrence at or around 6 months after BCG was initiated, and those who despite an initial 
complete response to BCG, relapse with high-grade NMIBC within 6 months of their last 
intravesical treatment with BCG (Lerner et al. 2015). Furthermore, the guidance states that for 
patients with unresponsive NMIBC for whom no standard therapy apart from radical cystectomy 


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exists, a single-arm study design is appropriate, and the complete response rate and duration 
of complete response are relevant efficacy endpoints in patients with CIS.   
The FDA guidance was finalized in February 2018 (FDA 2018).  This guidance further 
emphasized the study of CIS patients in single-arm trials and provides more detailed definitions 
of BCG-unresponsive disease and adequate BCG therapy.  The definition provided for the BCG-
unresponsive population was clarified, with the Agency recommending that the definition of 
treatment failure apply to patients who had failed one induction and one maintenance course of 
BCG at a minimum. In addition, it specified that a single-arm trial in the BCG-unresponsive 
patient population should employ a primary endpoint of complete response in CIS patients. This 
guidance informs the design of this study of the investigational agent BC-819 for the 
BCG-unresponsive NMIBC population. 
7.2 
BC-819 Background 
The biologically active ingredient of BC-819 (inodiftagene vixteplasmid) is a recombinant DNA 
plasmid (BC-819 drug substance [DS]) that directs the expression of a potent toxin specifically 
in malignant cells but not in normal tissue.  It has been designed to exploit the established 
biology of the H19 gene, which is upregulated and expressed at high levels only in malignant 
cells, and to incorporate technology that enables the delivery of a sequence that encodes for a 
lethal bacterial toxin from diphtheria so that the toxin is specifically expressed and activated only 
in bladder cancer tissue.  Uptake into malignant cells has been optimized by complexing the 
recombinant DNA plasmid with a transfection reagent (polyethylenimine [PEI]) to best facilitate 
entry of the recombinant molecule into cells.  The resultant drug product (BC-819/PEI) is 
administered intravesically to enable maximal topical exposure with target bladder cancer cells.    
H19 is a long non-coding RNA that has a restricted pattern of expression rendering it potentially 
useful for the targeted delivery of therapies to cancer (Matouk et al. 2013).  H19 is an oncofetal 
RNA gene highly expressed in the placenta but not normally expressed in adult tissues (Matouk 
et al. 2005).  However, its expression is upregulated in malignancy, and most human bladder 
cancers (Ohana et al. 1999; Luo et al. 2013) as well as in many other tumors.  The abnormal 
upregulation of H19 expression in malignancy is at least partly consequent to alterations in 
transcription factor availability and activity, and the regulatory controlling sequences of the H19 
promoter and enhancer that respond to these factors have been characterized (Kopf et al. 1998; 
Yoo-Warren et al. 1988; Ohana et al. 1999).  Key transcription factors known to be deregulated 
in cancer and function as modulators of H19 promoter activity and H19 expression have been 
identified (including E2F, P53, HIF1, and Slug) (Berteaux et al, 2005; Dugimont et al, 1998; Wu 
et al. 2017, Matouk et al. 2014). Thus, these regulatory elements can be used to control cytotoxic 
gene expression in a manner that prevents transcription in normal tissues and drives expression at 
significant levels in malignant cells that express H19. 
Diphtheria toxin is a potent cellular toxin and exhibits several characteristics that make it a 
favorable choice for anti-cancer transcriptional targeting.  Its biology and mechanisms of action 
are well understood; it is a 58 kDa protein that catalyzes the transfer of an adenosine 
diphosphate-ribose group from nicotinamide adenine dinucleotide to the protein translation 
factor EF2, inhibiting all protein translation (Bell and Eisenberg 1996).  Single copies of this 
toxin are lethal to a cell.  Moreover, the inhibitory activity of the toxin is encompassed in the 
A chain (diphtheria toxin A [DTA] 21 kDa), while the B chain is necessary for cellular entry.  


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Thus, cellular introduction and expression of the gene encoding and expressing DTA is lethal to 
the target cell but not to surrounding cells.   
BC-819 has been designed to exploit the specificity of H19 activation to express DTA in bladder 
cancer cells.  BC-819 DS is a double-stranded DNA plasmid 4560 base pairs in length.  It has 
been engineered using recombinant DNA technology so that 832 base pairs of H19 regulatory 
sequences (787 upstream and 45 downstream of the transcription start site) regulate the 
expression of DTA gene.  These regulatory sequences have been shown to direct gene expression 
specifically in bladder cancer cells (Ohana et al. 2002; Ohana et al. 2004).  The plasmid also 
contains the kanamycin-resistance gene that allows selection of plasmid-containing Escherichia 
coli bacterial cells so that the plasmid can be produced in large-scale bacterial cultures.  
PEI is a cationic polymeric moiety that efficiently facilitates the entry of BC-819 into rapidly 
dividing cells and improves efficiency of transfection both in vitro and in vivo in a variety of 
cellular and animal models, including bladder cancer.  It is complexed with the BC-819 DS in a 
fixed molar ratio during the manufacturing of the drug product.  Experiments in vitro 
demonstrate that BC-819 complexed with PEI is efficiently taken into more than 85% of cells 
following a single transfection.  In this protocol, the term BC-819 will hereafter be used to refer 
to the plasmid/PEI complex prepared for clinical administration. 
When transfected into a tumor containing H19 expressing cells, BC-819 becomes 
transcriptionally active, producing RNA for DTA, which is then translated into the lethal 
diphtheria toxin.  Following intravesical administration, cellular toxicity due to DTA expression 
is bladder cancer‒specific.  H19 is expressed in adults mostly in malignant tissue; thus, plasmid 
taken up in normal cells should remain unexpressed.  In addition, due to the absence of the B 
chain subunit, if toxin is released from dying cells it is not taken up by other normal cells.  Thus, 
BC-819 is a specifically targeted therapy for bladder cancer.  Studies have demonstrated that 
BC-819 DNA is detectable after intravesical administration for more than 48 hours in urine and 
in bladder tumors in patients (Ohana et al. 2004) and that DTA transcription is detectable after 
intravesical administration in experimental rat bladder tumors (Ohana et al. 2004).  In vitro 
studies have also confirmed that protein synthesis is inhibited in tumor cells transfected with BC-
819 (Ohana et al. 2002; Ohana et al. 2004).  
In animal models, BC-819 is active against bladder cancer.  In an orthotopic rat tumor model 
(Ohana et al. 2004), it was shown that syngeneic bladder tumors (Nara Bladder Tumor No. 2 
cells) growing in the bladder could be effectively treated with 2 intravesical administrations of 
BC-819.  In vitro studies with this cell line confirmed that the mechanism of action is via the 
dose-dependent expression of DTA chain driven by the H19 regulatory sequencing.  Additional 
studies employed a model of bladder carcinogenesis due to the ingestion of nitrosamine by rats.  
In this experimental model, rats reproducibly develop visible bladder tumors after approximately 
20 weeks of nitrosamine dietary supplementation.  Intravesical administration of BC-819 is 
effective in reducing mean tumor dimensions and weight and leads to complete eradication of 
tumors in some animals.  These data formed the basis for the initial clinical development of BC-
819 in patients with bladder cancer.  
7.3 
BC-819:  Clinical Studies in Patients With Bladder Cancer 
Two clinical studies (one Phase 1 study and one Phase 2 study) of the intravesical administration 
of BC-819 as a single agent have been completed to date in patients with NMIBC.  Additionally, 


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a Phase 2 combination therapy study of the administration of BC-819 and BCG has also 
been completed. 
7.3.1 
Phase 1 Study 
The initial Phase 1 study was a dose-escalation study that enrolled patients with recurrent 
low-grade NMIBC (Sidi et al. 2008).  At entry in this study, patients underwent resection of all 
disease except 1 marker lesion 0.5 to 1.0 cm in size.  Patients were then treated with intravesical 
BC-819 weekly for 3 weeks followed by a 1-week break and an additional 3 weekly treatments.  
Seven weeks later, patients who had not progressed were allowed to continue receiving 
maintenance therapy of BC-819 in 3 weekly instillations every 12 weeks.  The response of the 
marker lesion was assessed at 12 weeks, and residual tumor was removed at that time.  Resected 
tumors were assessed for H19 expression.  
A total of 18 patients were treated with escalating doses by cohort of BC-819 at the 2-, 4-, 6-, 
and 12-mg dose (n=3 in each cohort) and at the 20-mg dose (n=6).  Dose escalation was to 
continue until dose-limiting toxicity, defined as Grade 3 or worse (National Cancer Institute 
Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) adverse event (AE) at 
least possibly related to study medication, occurred during the first 3-week course of treatment or 
the immediate follow-up period before repeat dosing.  The mean age of patients was 71 years 
(range: 49 to 82 years); 83% were male.  Patients had a mean of 5 prior occurrences (range: 1 to 
15 occurrences).  Ten of 18 patients (56%) had ≥2 recurrences in the past 2 years.  Seventeen 
patients (94%) had received prior BCG, and several patients had also received various 
chemotherapeutic agents. 
No dose-limiting toxicities were observed or reported, and no deaths occurred during the study 
or during the follow-up period.  Intravesical administration of BC-819 at doses from 2 mg to 
20 mg plasmid weekly for 6 weeks was well tolerated.  The most frequently reported AEs 
considered to be at least possibly related to investigational product for any dose cohort were mild 
to moderate in severity and were most commonly renal and urinary disorders.  Mild bladder 
discomfort and dysuria were reported in 11.1% and 16.7% of patients, respectively.  Moderate 
dysuria and micturition urgency were reported in 5.6 % and 16.7% of patients, respectively.  
Severe (Grade 3) micturition urgency was reported by 1 patient in the 6-mg dose cohort after the 
fourth intravesical treatment.  In total, 44% of patients had a urinary tract infection during the 
study, of which 17% were considered related to other investigational procedures such as the 
video-cystoscopy, catheterization, or surgical resection.  Mild (Grade 1) diarrhea, hypertension, 
and asthenia were reported in 11.1%, 16.7 %, and 11.1% of patients, respectively.  Laboratory 
AEs considered possibly related to treatment included increased blood creatinine and leukopenia 
in 22.2% and 11.1% of patients, respectively.  There was no dose-response relationship in overall 
AEs (related + nonrelated).  One serious adverse event (SAE) considered possibly related to 
study treatment, urinary urgency requiring hospitalization, occurred in the study.  This SAE 
occurred in a patient in the 6-mg weekly treatment group. 
The primary efficacy assessment was overall response rate (complete and partial) as directly 
visualized by cystoscopy at Week 12; in 4 of 18 patients (22%), complete responses were 
observed.  In an additional 4 of 18 patients (22%), partial responses were observed.  Thus, total 
responses were observed in 8 of 18 patients (44%).  Median time to recurrence among all 
18 study patients and across all dosing levels was 5.7 months (95% CI was 4.1 to 11.6 months).  


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H19 expression was detected in all tumors at baseline. 12/18 (66.7%) of the patients were 
recurrence-free at 3 months, and 44.4% and 33.3% were recurrence-free at 12 months and 
24 months respectively. 
In summary, the maximum tolerated dose for weekly BC-819 administration was not identified, 
and 20 mg was identified as the dose for further study.  Higher doses (>20 mg) could not be 
administered because of volume constraints.  AEs were generally mild to moderate; most may 
have been related either to study drug or to the catheterization and treatment procedure.  Anti-
tumor activity was evident, and complete and partial responses against existing macroscopic 
tumors were observed.  Although the sample size was small, there was no suggestion of a dose-
response effect with regard to either efficacy or safety. 
7.3.2 
Phase 2 Monotherapy Study 
Following the Phase 1 study, a Phase 2 study of BC-819 was completed in patients with 
superficial bladder cancer of intermediate risk.  The primary endpoint in this study was to 
determine tumor recurrence in resected patients; a secondary endpoint was response rate of 
marker lesions.  Patients with histologically confirmed superficial bladder cancer with recurrent 
stage Ta (any grade) or T1 (low-grade) NMIBC were eligible to enter the study.  Patients with 
CIS lesions were excluded.  All tumor specimens resected at baseline were H19 positive.  
Patients must have failed at least 1 prior conventional therapy including either BCG or 
chemotherapy and, as in the Phase 1 study, have 1 tumor ≤1.0 cm in diameter to serve as a 
“marker” tumor after removal of all other tumors.  Treatment in this study was composed of an 
initial induction phase of 6 weekly 20-mg instillations followed by safety and efficacy 
assessment at Week 9.  Subsequently, in the absence of recurrence or toxicity requiring 
discontinuation of therapy, these patients continued to receive maintenance therapy of 3 weekly 
courses every 12 weeks. 
A total of 47 patients were treated in this study; 38 patients (81%) received prior BCG, and 
more than half of the patients received other therapies as well (45% of patients received 2 or 
more prior treatments).  Eight patients were not evaluable due to protocol violations and 
early withdrawal.  
At the time of primary assessment at Week 9 after the start of treatment, 13 patients (28% of the 
intent-to-treat [ITT] population and 33% of the per-protocol population) had complete 
disappearance of the marker lesion, and no new lesions were reported.  Twenty-six patients 
(55%) in the ITT population and 64% of patients in the per-protocol population had no new 
lesions at 3 months (the primary endpoint).  Median time to recurrence for both the ITT and 
per-protocol populations was 11.3 months; 46% and 36% of patients were free of recurrence at 
12 and 18 months, respectively, and 33% remained recurrence-free at 24 months follow-up.  
Treatment was very well tolerated.  No patients discontinued because of treatment-related 
adverse events (TEAEs).   
The most commonly reported AEs were renal and urinary disorders, experienced by 30% of 
patients entered.  These included urinary frequency (15%), dysuria (11%), micturition urgency 
(6%), and urinary retention (6%).  Urinary tract infections, classified under infections and 
infestations, were reported by 11% of patients.  Other AEs experienced by 3 or more patients 
included increased blood potassium (11%) and asthenia, chills, pyrexia, and nausea (6%, each).  
No patients had an elevation of either creatinine or blood urea nitrogen levels.    


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Seven SAEs in 5 patients were reported:  1 patient developed urinary retention and a urinary tract 
infection and subsequently underwent TUR of the prostate; 1 patient developed a myocardial 
infarction; 1 patient developed hematuria; 1 patient developed pneumonia; and 1 patient had an 
exacerbation of pre-existing chronic obstructive pulmonary disease.  Only the event of hematuria 
was considered by the treating investigator to be possibly related to study treatment, though also 
probably related to study procedure.  SAEs in the other 4 patients were considered unrelated to 
study medication or procedure; 2 patients were screen failures who never received any 
study drug. 
7.4 
Phase 2 Combination Study 
Additionally, a Phase 2 study was completed in 38 patients eligible for BCG treatment.  Three 
different combination schedules were evaluated with a primary objective of evaluating the safety 
of the combination.  All 3 schedules were well tolerated, with 3 SAEs reported, none of which 
was considered related to BC-819.  
Tumor recurrence rate and progressive disease rate were not statistically significantly different 
among the 3 regimens.  The overall recurrence-free survival rate was 54%, and the 
progression-free survival (PFS) rate was 75%.  At 18 months of follow-up, the median time to 
recurrence and its confidence limits could not be calculated according to Kaplan-Meier survival 
analysis because a large percentage of patients had no recurrence.  Because of the small number 
of patients, the optimal schedule could not be determined. 
The safety and tolerability of combined therapy with BC-819/PEI and BCG were determined by 
reported AEs, physical examinations, vital signs, and laboratory tests.  Patients who received any 
study medication (even a partial dose) were considered evaluable for safety. 
Administration of BC-819/PEI+BCG was well tolerated. Overall, 65.8% (25/38) of patients 
experienced AEs during the study.  The incidence of AEs was similar among the treatment 
groups and most AEs were mild.  The most common AEs were renal and urinary disorders.  The 
incidence of BC-819/PEI-related AEs was lower than that of BCG-related AEs (10.5% vs 
26.3%).  Only 1 patient had a procedure-related AE (pain in extremity).  No patients withdrew 
because of AEs. 
Three SAEs occurred during the study.  None of them were related to BC-819/PEI or to BCG or 
to the procedure. Two of the SAEs, mild palpitations and moderate urinary tract disorder, 
resolved without sequelae.  One patient had severe pulmonary edema that resulted in death.  
7.5 
Rationale for Study 
The population for this study is patients with high-risk NMIBC whose disease is unresponsive to 
BCG.  This is a patient population for which treatment options are limited and outcomes are 
usually poor.  As reviewed above, patients whose disease is unresponsive to BCG have poor 
options for medical therapy, with outcomes suggesting 2-year disease-free survival ranging from 
2% to 20%. Standard of care is therefore radical cystectomy.  As summarized above, the AUA 
and FDA jointly convened a workshop to address the development of new therapies in NMIBC, 
specifically addressing patients who have repeatedly failed BCG therapy (Jarow et al. 2014).  In 
November 2016, the FDA issued a second, more detailed guidance document for drug 
development in this specific population, which was finalized in February 2018.  These guidance 


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documents state that for such patients, no standard of care could be identified that would serve as 
a control population for a randomized clinical study.  Therefore, in this setting, a single-arm 
Phase 2 clinical study with complete response rate as the primary endpoint can provide primary 
evidence of effectiveness to support a marketing application.  This Phase 2, single-arm, open-
label study of BC-819 in patients who have high-risk NMIBC that is unresponsive to BCG has 
been designed with these guidelines in mind.   
The Phase 1/2 and Phase 2 studies described above provide preliminary clinical evidence in 
support of this study.  While the Phase 2 study patients did not fit the definition of 
BCG-unresponsive used in the proposed study, these patients were still quite heavily pretreated, 
with more than half of the patients receiving not only BCG but, in most cases, cytotoxic drugs as 
well; 45% had received 2 or more prior therapies.  Furthermore, 67% had experienced 2 or more 
prior recurrences in the 2 years before study start.  By ITT analysis of all patients entered in the 
Phase 2 study, median time to recurrence was 11.3 months (95% CI of 5.3 to 7.2 months).  
Forty-six percent (46%) of the ITT population was free of recurrence at 12 months. 
The primary endpoint of this study will be to determine in patients with baseline CIS, the 
proportion of patients that experiences a complete response (CR).  In this study, in accordance 
with the FDA guidance, complete response is defined as negative urine cytology and no lesions 
visible on cystoscopy, negative urine cytology with biopsy proven benign or low-grade NMIBC, 
or negative cystoscopy with malignant urine cytology, if cancer is found in the upper tract or 
prostatic urethra and random bladder biopsies are negative.  Additionally, the duration of the 
response will be determined.  Recurrence is defined as the reappearance or persistence of high-
grade disease. Recurrence must be biopsy proven.  Persistence, appearance, or presence of lower 
grade disease will not be considered recurrence.  Additionally, patients with appearance of new 
high-grade disease (ie, new high-grade papillary disease in patients with CIS only or new CIS in 
patients with papillary disease only) will be classified as failures, as will patients with CIS at 
baseline whose CIS lesions have not resolved by the 12-week cystoscopy or who have CIS or 
high-grade papillary disease at later timepoints.   
High-risk recurrences are the most important predictors of risk of tumor progression.  Patients 
who recur with only low-grade recurrence will not be considered treatment failures and may 
continue study participation after standard-of-care resection of the new lesion(s), if any.  
Sylvester et al. (2006) developed a model for predicting recurrence and progression in NMIBC.  
In this model, which included tumor grade, low-grade tumors, there was a low potential for 
progression.  Fernandez-Gomez et al. (2009) used a similar approach and considered a 
population in which all patients had been treated with BCG.  These analyses demonstrated that 
high-grade tumor was a moderate risk factor for recurrence but a very strong risk factor for 
progression.  Conversely, presence of low-grade tumor had little effect on progression.  
Therefore, the primary target population for this study focuses on patients with elevated risk for 
progression and comprises patients with high-risk/grade NMIBC that is BCG-unresponsive. 
 
 


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8. 
STUDY OBJECTIVES 
8.1 
Primary Objectives 
The primary objective is to determine, for the patients with baseline CIS: 
• The proportion that achieves a complete response (CR) after treatment with inodiftagene 
vixteplasmid 
8.2 
Secondary Objectives 
The secondary objectives are to determine the: 
• Proportion of patients with absence of high-grade recurrent or persistent disease at 
48 weeks (overall population and subgroup of patients with CIS) 
• Proportion of patients with absence of high-grade recurrent or persistent disease at 12, 24, 
36, 72, and 96 weeks (overall population and subgroup of patients with CIS) 
• Time to recurrence (Kaplan-Meier plot) 
• Proportion of patients who are progression-free at 48, 72, and 96 weeks 
• Overall survival of patients enrolled in the study at 48, 72, and 96 weeks 
• Quality of life in patients treated with inodiftagene vixteplasmid 
• Assessment of safety 
 
 


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9. 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan—Description 
This study, BC-819-18-204 (referred to as Study 204), is a Phase 2, open-label, monotherapy, 
single-arm, multicenter clinical trial of BC-819 (inodiftagene vixteplasmid) in patients with 
NMIBC adequately treated with BCG whose disease is BCG-unresponsive according to the FDA 
guidance (FDA 2018).  Patients with BCG-unresponsive disease have NMIBC that is unlikely to 
benefit from and should not be treated with further intravesical BCG.  
Patients are to have recurred or progressed after adequate treatment, had BCG-unresponsive 
disease, had a TUR, and then had all papillary disease completely resected and obvious CIS 
disease fulgurated when indicated.  Patients with T1 disease should undergo resection of the base 
of the lesion when possible (biopsy should contain muscle fiber).  Patients must have 1 or more 
of the following: completely resected high-grade T1 disease, CIS disease, or completely resected 
high-grade Ta disease.  There is no intravesical or medical standard of care for this patient 
population, and the usual course is radical cystectomy. 
A total of 140 patients who meet study entry criteria will be enrolled and treated during the 
approximately 15-month enrollment period.  The first 35 patients enrolled and treated must have 
CIS (with or without papillary disease).  After these 35 patients are treated and 10 complete 
responders are documented, the enrollment will expand to also allow patients with papillary 
disease only who meet inclusion and exclusion criteria.  It is estimate that a total of 
approximately 70 to 100 patients with CIS will be treated.   
All enrolled patients will enter the 10-week induction phase and begin treatment with BC-819.  
Treatment should begin within 7 days of enrollment and ≤42 days from the last TUR or biopsy.  
During the induction phase, patients will receive an intravesical instillation of BC-819 at a dose 
of 20 mg/50 mL aqueous solution once per week for 10 weeks according to the induction phase 
treatment schedule (see Table 12.1). 
Upon completion of the induction phase, patients will continue with maintenance therapy of 
BC-819 every 3 weeks beginning at Week 12 (Visit 11) and continuing for the next 84 additional 
weeks until the end of the study, defined as completion of the 96-week visit (Visit 39).   
During the study, patients will undergo repeat direct visualization (ie, cystoscopy ± biopsy and 
cytology) and re-TUR (as needed for cause) every 12 weeks during the first and second year.  
Patients with persistent CIS which does not resolve by the 12-week assessment, or at subsequent 
12-week assessments, or who have recurrence or new evidence of CIS or high-grade papillary 
disease at any time will be discontinued and classified as nonresponders and recurrences in the 
primary and secondary endpoint analyses.  Patients benefiting from treatment, with no 
documented high-grade recurrence or progression, will continue to receive maintenance therapy 
every three weeks.  Appearance or persistence of lower grade tumors will not be considered as 
recurrence for the primary and secondary endpoint analyses, and patients with only low-grade 
tumors should continue treatment after resection and histological confirmation.  
9.2 
Discussion of Study Design and Choice of Control Group(s) 
The presentations and discussion at a workshop held at the annual AUA meeting in May 2013 
serve as the rationale for this study.  A summary of that meeting was published by Jarow et al. 


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(2014).  The FDA recently published a more detailed guidance document in February 2018 that 
reiterates the challenges for drug development in this specific population, clearly stating that 
there is currently no effective therapy for patients with high-grade NMIBC unresponsive to BCG 
other than cystectomy (FDA 2018).  Therefore, a single-arm Phase 2 clinical study is acceptable. 
9.3 
Selection of Study Population 
Eligible patients must be BCG-unresponsive, adequately treated, who after recurrence have had 
all papillary disease resected and CIS fulgurated when indicated.   
9.3.1 
Inclusion Criteria 
Eligible patients must meet the following inclusion criteria: 
1. Male or female patients ≥18 years of age at the time of consent
2. Patient must have been adequately treated with BCG defined as at least one of the
following (FDA 2018):
a.
At least five of six doses of an initial induction course plus at least two of three
doses of maintenance therapy
b.
At least five of six doses of an initial induction course plus at least two of six
doses of a second induction course
c.
A single course of induction BCG can qualify if the patient has T1 high-grade
disease at first evaluation (see 3c)
3. Patient must be BCG-unresponsive according to the FDA guidance defined as at least one
of the following (FDA 2018):
a.
Persistent or recurrent CIS alone or with recurrent Ta/T1 disease within
12 months of completion of adequate BCG therapy.  An assessment within
15 months can also qualify when no assessment was done 12 months after
completion of adequate BCG therapy.
b.
Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate
BCG therapy.  An assessment within 9 months can also qualify when no
assessment was done 6 months after completion of adequate BCG therapy.
c.
T1 high-grade disease at the first evaluation following a single course of induction
BCG qualifies (Lerner et al. 2015, Steinberg et al. 2016)
4. Patient must have, at study entry, NMIBC indicated by 1 or more of the following:
a.
Ta or T1 high-grade disease
i. No more than 42 days may elapse between the start of protocol therapy
and complete resection of Ta/T1 papillary disease qualifying the patient
for the study
b. CIS disease
i. Obvious areas of CIS should be fulgurated prior to start of therapy
when indicated
5. Patient must have no known evidence of concomitant upper tract urothelial carcinoma or
urothelial carcinoma within the prostatic urethra within 6 months of enrollment
6. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance
status ≤2


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7. Patient must have adequate hematologic function, as demonstrated by the following: 
a. Hemoglobin level ≥10 g/dL 
b. Absolute neutrophil count ≥1.5 x 109/L 
c. Platelet count ≥100 x 109/L 
8. Patient must have adequate liver and renal function as demonstrated by the following: 
a. Aspartate aminotransferase and alanine aminotransferase each ≤3.0 x upper limit 
of normal 
b. Total bilirubin ≤1.5 x upper limit of normal, unless prior documentation of 
Gilbert’s syndrome in which case, 3.0 mg/dL is allowed 
c. Serum creatinine ≤1.5 x upper limit of normal or measured or calculated 
creatinine clearance ≥30 mL/min  
9. Female patients of childbearing potential must use maximally effective birth control 
during the period of therapy (ie, a combination of 2 regulatory approved methods), must 
be willing to use contraception for 1 month after the last study drug infusion, and must 
have a negative urine or serum pregnancy test result upon entry into the study.  
Otherwise, female patients must be postmenopausal (no menstrual period for a minimum 
of 12 months) or surgically sterile   
10. Male patients who are sexually active must be willing to use a double-barrier 
contraceptive method upon study enrollment, during the course of the study, and for 
1 month after the last study drug infusion 
11. Patient must be able to understand and sign an ICF  
12. Patient must be able to comply with protocol requirements, including attendance at 
required clinic visits 
9.3.2 
Exclusion Criteria 
The presence of any of the following excludes a patient from study enrollment: 
1. Patient has current or previous evidence of muscle invasive (muscularis propria) or 
metastatic bladder cancer disease  
2. Patient has received prior investigational therapy for NMIBC 
3. Patient has received any therapy for NMIBC within 10 weeks before the start of study 
treatment other than surgical resection, 1 dose of chemotherapy, and previous BCG 
4. Patient is intolerant to previous BCG treatment in the absence of meeting other criteria 
for BCG unresponsiveness and adequate BCG therapy  
5. Patient has received external beam radiation therapy for bladder cancer at any time or for 
any other condition  
6. Patient has an active infection, including urinary tract infection (viral, bacterial, or 
fungal) and cystitis 
7. Patient has urinary tract signs or symptoms that preclude retention of drug in the bladder; 
this does not include anticholinergic drugs  
8. Patient is known to have tested positive for human immunodeficiency virus (HIV).  No 
HIV testing is required if patient is not known have tested positive 


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9. Patient is female and is pregnant or breastfeeding 
10. Patient has any medical, psychological, or social condition or situation that may, in the 
investigator’s opinion, make it difficult for the patient to tolerate study medication or 
comply with study procedures and other requirements.  This includes but is not limited to 
active infections, poorly controlled diabetes, uncontrolled cardiac arrhythmia, angina 
pectoris, or hypertension 
11. Patient has a known presence or history of malignancy of other organ system within the 
5 years before study start, with the exception of non-melanoma skin cancer (eg, basal cell 
carcinoma or squamous cell carcinoma of the skin); very low or low-risk prostate cancer 
(by National Comprehensive Cancer Network guidelines) defined as prostate-specific 
antigen <10 ng/dL, Gleason score ≤6, and clinical stage T1c; or patients who have been 
disease-free for at least 2 years following stage 1 or 2 cancer 
12. Patient is on immunosuppressive therapy or has had a transplant within 12 months before 
study start, except for chronic use of corticosteroids (eg, rheumatoid arthritis, asthma, 
chronic obstructive pulmonary disease, or any other similarly chronic use of steroids) 
13. Patient has any other significant disease that, in the opinion of the investigator, would 
prevent study entry 
 
9.4 
Study Treatment Plan 
9.4.1 
Enrollment Period  
At study entry, patients with BCG-unresponsive disease can have completely resected papillary 
disease, resected papillary disease with CIS, or CIS alone.  It is required that the first 35 patients 
treated have CIS (with or without papillary disease). 
To fully define the extent of disease at study entry, eligible patients must have had a recent TUR 
(within 6 weeks/42 days) prior to start of treatment.  No more than 42 days may elapse between 
complete resection of papillary disease and start of therapy.  Patients with T1 disease should 
undergo resection at the base of the lesion to ensure the absence of muscle-invasive disease.  
Patients for whom the last TUR was performed by a study investigator (or an on-site designee) 
≤42 days before the first study treatment are not required to have a re-TUR.  It is recommended 
that patients who had a TUR performed elsewhere and/or patients with high-grade disease at 
baseline (high-grade Ta, high-grade T1, or Tis) have a re-TUR performed ≤42 days before the 
first study treatment to exclude any visibly growing stage Ta or T1 papillary tumors (in which 
case, re-TUR is indicated), remaining CIS lesions, and/or exclude T2 (muscle-invasive) disease.  
Any visible CIS lesions should be fulgurated at that time as needed.  
Patients should be staged before enrollment.  Staging should include the use of bladder mapping 
and random biopsies in patients with CIS or high-grade papillary disease (Gudjonsson et al. 
2012).  In this study, tumor staging will be conducted in accordance with the AUA-adopted 
TNM staging classification (Sobin et al. 2009), and grading will follow the World Health 
Organization (WHO) grading classification (2004 revision, Miyamoto et al. 2010) with tumors 
categorized as papillary urothelial neoplasm of low malignant potential, low-grade, or high-
grade.  TNM classifications are shown in Table 9.1. 
Urine cytology results should also be obtained and evaluated prior to enrollment. 


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Table 9.1. 
TNM Staging Classifications 
T - Primary Tumor 
N – Lymph Nodes 
M - Distant Metastasis 
Ta: Noninvasive papillary 
carcinoma 
Nx: Regional lymph nodes 
cannot be assessed 
M0: No distant metastasis 
Tis: Carcinoma in situ 
N0: No regional lymph node 
metastases 
M1: Distant metastasis 
T1: Tumor invades sub-
epithelial connective tissue 
N1: Metastasis in a single 
lymph node in the true pelvis 
(hypogastric, obturator, 
external iliac, or presacral) 
T2: Tumor invades 
muscularis 
•
T2a: Superficial muscle
(inner half)
•
T2b: Deep muscle (outer
half)
N2: Metastasis in multiple 
lymph nodes in the true pelvis 
T3: Tumor invades peri-
vesical tissue (beyond 
muscularis) 
•
T3a: Microscopically
•
T3b: Macroscopically
(extravesical mass)
N3: Metastasis in a common 
iliac lymph node 
T4: Tumor invades any of the 
following: prostate, uterus, 
vagina, pelvic wall, 
abdominal wall 
•
T4a: Prostate, uterus,
vagina
•
T4b: Pelvic wall,
abdominal wall
Source:  Sobin et al. 2009. 


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Administration of BC-819 During Treatment Sessions 
During treatment sessions, patients are encouraged to minimize fluid intake for 6 hours before 
instillation of the study medication and for 2 hours thereafter or until voiding, whichever 
comes first. 
At each treatment session, a thin, sterile tube (called a Foley catheter) will be inserted into the 
bladder to drain urine and serve as a port of entry for the planned bladder instillations.  Size 
12-Fr (1 "French" or "Fr" = 0.33 mm = .013") catheters are normally suggested, but use of other 
sizes is acceptable per the investigator’s discretion. Should the patient have an enlarged prostate 
(eg, benign prostatic hyperplasia) or any other condition that may obstruct the urethra, a Coudé-
tipped catheter (called a Tiemann catheter) angled upward at the tip may be used to assist in 
negotiating the upward bend in the male urethra in order to completely drain the bladder.  Size 
10-Fr catheters are normally suggested for this scenario, but use of other sizes is acceptable.  
A 20-mg dose of BC-819 in a total volume of 50 mL will then be instilled into the bladder over 
approximately 4 minutes.  After infusion, a further saline/sterile water flush may be needed to 
ensure that the BC-819 sitting in the catheter tubing is also flushed into the bladder space 
ensuring that full dose is delivered. The drug should be retained in the bladder for as long as 
possible (for a maximum of 2 hours but not less than 30 minutes) to allow for good topical 
contact between the drug and the inner bladder epithelium, which results in improved penetration 
(also referred to as plasmid transfection) of the drug into the cells through 1 or more bladder 
inner wall layers.  The time that the instillation is completed and the time of postdose voiding 
should be recorded in the source documents.   
9.4.2 
Induction Phase 
Study treatment will start within 7 days of enrollment and ≤42 days from the last TUR or biopsy.  
Initial therapy begins with a 10-week induction phase.  Patients will receive an intravesical 
installation of BC-819 20 mg/50 mL once per week for 10 weeks during this phase.  
9.4.3 
Maintenance Treatment 
Upon completion of the induction phase, patients will transition to a maintenance therapy 
schedule of BC-819 (ie, once every 3 weeks).  The first maintenance treatment and visit will 
occur 12 weeks after enrollment (Visit 11).  Treatments will continue every 3 weeks for 84 
additional weeks until the end of the study (end of study [EOS] Visit 39) at 96 weeks.   
Patients who have recurred with high-grade papillary carcinoma or with metastatic disease will 
be considered treatment failures and will be withdrawn from the study.  All suspected 
recurrences (by direct visualization) must be documented by biopsy results.    
Patients who are free of high-grade tumors or who are tumor-free (ie, patients benefiting from 
treatment) will be allowed to continue to receive maintenance therapy every 3 weeks per the 
schedule of treatment during the maintenance phase (Table 12.2 and Table 12.3) as long as 
response status is maintained and they are not considered a treatment failure.   
Patients will undergo repeat direct visualization (ie, cystoscopy ± biopsy and cytology) and 
re-TUR (as needed for cause) every 12 weeks during the first and second year of the study.  
All enrolled patients will complete the following quality of life questionnaires at the visits 
indicated in the study schedule (Table 12.1 and Table 12.2):  


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• The European Organization for Research and Treatment of Cancer quality of life 
Questionnaire (EORTC QLQ-C30; a general questionnaire for cancer) 
• Quality of Life Questionnaire–Non-Muscle-Invasive Bladder Cancer Questionnaire 
(QLQ-NMIBC24; a specific questionnaire for NMIBC disease) 
The end of the study will be the 96-week visit (Visit 39) for all patients.   
Maintenance Treatment and Repeat Direct Visualization Schedule 
Patients benefiting from treatment with no documented progression or high-grade recurrence will 
continue to receive maintenance therapy every 3 weeks starting from Visit 11 (Week 12) 
onward.  
During the first-year maintenance treatment, patients will continue treatment with BC-819 every 
3 weeks as listed below: 
• Visit 11 or 12 weeks (3 months) 
• Visit 12 or 15 weeks  
• Visit 13 or 18 weeks 
• Visit 14 or 21 weeks  
• Visit 15 or 24 weeks (6 months) 
• Visit 16 or 27 weeks  
• Visit 17 or 30 weeks  
• Visit 18 or 33 weeks  
• Visit 19 or 36 weeks  
• Visit 20 or 39 weeks  
• Visit 21 or 42 weeks 
• Visit 22 or 45 weeks 
• Visit 23 or 48 weeks (12 months) 
As mentioned above, urine cytology, cystoscopy, and re-TUR (as needed for cause) will be 
performed every 12 weeks (within 2 weeks prior to the maintenance treatment) during the first 
year of the study (in alignment with the AUA standard of care) and are required before the 
maintenance treatment at the following visits:  
• Visit 11 or 12 weeks (3 months) 
• Visit 15 or 24 weeks (6 months) 
• Visit 19 or 36 weeks  
• Visit 23 or 48 weeks (12 months) 
The 12-week visit (Visit 11) will include the initial evaluation of the primary endpoint of 
complete response rate in CIS patients.   
During the second year of maintenance treatment, patients will continue treatment with BC-819 
every 3 weeks as listed below: 


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• Visit 24 or 51 weeks 
• Visit 25 or 54 weeks  
• Visit 26 or 57 weeks  
• Visit 27 or 60 weeks  
• Visit 28 or 63 weeks  
• Visit 29 or 66 weeks 
• Visit 30 or 69 weeks 
• Visit 31 or 72 weeks (18 months) 
• Visit 32 or 75 weeks  
• Visit 33 or 78 weeks  
• Visit 34 or 81 weeks  
• Visit 35 or 84 weeks  
• Visit 36 or 87 weeks  
• Visit 37 or 90 weeks 
• Visit 38 or 93 weeks 
• Visit 39 or 96 weeks (24 months) – end of study assessments with no treatment 
Mandatory second year cystoscopy should be performed within 2 weeks prior to the following 
visits and is required before the maintenance treatment:   
• Visit 27 or 60 weeks  
• Visit 31 or 72 weeks (18 months) 
• Visit 35 or 84 weeks  
• Visit 39 or 96 weeks (24 months) 
9.5 
Dosing Delays 
All toxicity in this study will be graded in accordance with CTCAE guidelines (version 5.0). 
• No dose reduction of BC-819 is planned 
• No dose adjustments are allowed 
• A delay of up to 2 weeks from the scheduled treatment (≤2 weeks) is allowed at the 
investigator’s discretion   
• Administration of any missed doses should be discussed with and approved by the 
sponsor medical monitor or delegate 
• Skipped doses or termination of treatment will be based on the observed toxicities (as 
specified below) 
Grade 3 to 4 BC-819 related or unrelated AEs should be managed as follows: 
• First occurrence of Grade 3 or 4 toxicity—withhold treatment until toxicity has improved 
to Grade ≤1 
• Second occurrence: 


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o Of Grade 3 toxicity—withhold treatment until toxicity has improved to Grade ≤1 
o Of Grade 4 toxicity—permanently discontinue treatment 
• Third occurrence of Grade 3 toxicity—permanently discontinue treatment 
Types of AEs that would warrant withholding treatment include but are not necessarily limited to 
persistent irritative symptoms lasting >48 hours, fever >100°F (37.8°C), sepsis, and hematuria.  
Patients should be reassessed at 1-week intervals until the applicable AE has resolved, up to a 
maximum delay of 5 weeks.   
During the induction phase, the investigator may skip only 1 scheduled induction treatment 
because of a toxicity-related delay without disqualifying the patient from the study and 
warranting study withdrawal.  All enrolled patients must receive a minimum of 5 of the planned 
6 induction phase BC-819 instillations.  Patients requiring more than 1 scheduled induction 
treatment to be skipped will require sponsor medical monitor or delegate approval to continue 
study participation.  During the maintenance phase of the study, investigators may withhold 
treatment because of Grade 3 or 4 toxicity for 1 visit only. 
9.6 
Discontinuation of Therapy 
Reasons for permanent discontinuation include the following: 
1. In patients with CIS at baseline, failure to clear CIS lesions by Week 12; however, patients 
who clear CIS lesions but have low-grade disease should continue to be treated.  Patients 
with CIS lesions that fail to clear may be followed by cystoscopy until they have a 
cystectomy or start an alternative treatment, but will be considered non-responders in the 
primary efficacy analysis  
2. Recurrence of high-grade papillary lesions at the Week 12 cystoscopy or later or of CIS 
lesions after clearance.  Only patients who meet the definition of recurrence should be 
discontinued.  Patients with persistence or appearance of lower grade disease should not 
be discontinued 
3. Unacceptable toxicity, defined as a persistent Grade 3 AE or higher despite dosing delay 
(according to the AE management guidelines in Section 9.5) 
4. Withdrawal of consent 
Any patient without tumor in the bladder but presence of tumor in the upper urinary tract will not 
be classified as a failure in primary analyses and will continue study participation. 
The reason for early discontinuation must be documented in the electronic case report form 
(eCRF). After discontinuation of study treatment for any reason, patients should be followed up 
for 30 days to assess safety. 
 
 


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10. 
STUDY PRODUCT 
10.1 
Study Medication Supply 
BC-819 will be supplied by the study sponsor.   
Study product is manufactured in accordance with current good manufacturing practices; the 
recombinant plasmid of BC-819 is manufactured by Boehringer-Ingelheim RCV, Vienna, 
Austria, and the transfection agent (PEI) by ChemCon GmbH, Freiburg, Germany. 
10.2 
Description of Study Product  
BC-819 vials contain a 5- mL dose of BC-819 at a concentration of 0.4 mg plasmid/mL in 5% 
trehalose solution.   
10.3 
Packaging and Labeling  
BC-819 is supplied as a single ready-to-use vial containing 50 mL BC-819 active plasmid and 
transfection agent complex at a concentration of 0.4 mg plasmid/mL in 5% trehalose solution.  
The product will be labelled according to local and national regulatory requirements. 
10.4 
Conditions for Storage and Use 
BC-819 must be stored in a temperature-controlled and monitored environment at 2oC to 8oC.  
10.5 
Method of Assigning Patients to Treatment Groups 
This is a single-arm study.  All patients will receive BC-819 according to the schedules shown in 
Section 12 (Table 12.1, Table 12.2, and Table 12.3). 
10.6 
A Dispensing, Compliance and Accountability 
All study medications will be administered in the clinic under the supervision of the investigator 
or his/her delegate.  Accordingly, compliance and accountability will be assessed from records of 
administration maintained by the investigational study team at each site. 
The investigator is responsible for maintaining accountability for the receipt, dispensing, and 
return of all study medication.  Maintenance of all required investigational medicinal product 
(IMP) records can be delegated by the investigator to a suitably qualified member of the 
investigational study team at each site. 
10.7 
Concomitant Therapy 
Patients may not receive other therapy for bladder cancer, either intravesical or systemic, except 
for anticholinergic treatment and/or chronic use of corticosteroids. 
Patients may receive therapy for AEs per investigator judgment. 
All concomitant medications, whether for TEAEs or other reasons, and the indications for their 
use must be recorded in the patient’s eCRF. 


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11. 
EFFICACY AND SAFETY ASSESSMENTS 
11.1 
Primary Efficacy Variable 
The primary efficacy endpoint is, in patients with CIS at baseline, the: 
• Proportion that achieves a CR at any time on or after week 12 and within the first 
48 weeks  
Complete response is defined as at least one of the following: 
• Negative cystoscopy and negative (including atypical) urine cytology 
• Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative 
cytology 
• Negative cystoscopy with malignant urine cytology if cancer is found in the upper tract or 
prostatic urethra and random bladder biopsies are negative 
The complete response in patients with CIS for this endpoint must be documented on or after the 
Week 12 response assessment and on or prior to the Week 48 assessment.  Duration of complete 
response in patients with CIS will be calculated from the documented onset of the complete 
response to the assessment where the patient no longer meets the definition of complete 
response.  More generally, recurrence is defined as the reappearance or persistence of high-grade 
disease, or new high-grade disease.  Recurrence must be biopsy proven.  Persistence, appearance, 
or presence of lower grade disease will not be considered recurrence.  
 
11.2 
Secondary Efficacy Variables 
The secondary endpoints include the following: 
• The incidence of EFS at 48 weeks, where EFS is defined as high-grade recurrence-free 
survival (overall population and subgroup of patients with CIS) 
• The incidence of EFS at 12, 24, 36, 72, and 96 weeks, where EFS is defined as high-
grade recurrence-free survival (overall population and subgroup of patients with CIS) 
• Time to recurrence; recurrence is defined as an EFS event  
• The incidence of PFS at 48, 72, and 96 weeks as well as time to progression estimated 
using Kaplan-Meir methods.  Progression is defined as the development of T2 or greater 
disease.  Sensitivity analyses will also be performed and will include any of the following 
as progressions: 
o An increase in stage from Ta or CIS to T1, or  
o Development of T2 or greater, or  
o Lymph node disease, or  
o Distant metastasis  
• Overall survival of patients enrolled in the study at 48, 72, and 96 weeks and survival 
time estimated using Kaplan-Meier methods 


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• Changes in quality of life over time, as measured by the EORTC QLQ-C30 (a 
general questionnaire for cancer) and the QLQ-NMIBC24 (a specific questionnaire 
for NMIBC disease) 
Additionally, patients with appearance of new high-grade disease (ie, new high-grade papillary 
disease in patients with CIS only or new CIS in patients with papillary disease only) will be 
classified as treatment failures in EFS analyses, as will patients with CIS at baseline whose CIS 
lesions have not resolved by the 12-week cystoscopy, or who have recurrent CIS at later 
cystoscopies.  
At each follow-up visit, response of existing lesions and presence of any new lesions will be 
evaluated (by direct visualization and biopsies as needed) and reported in the eCRF.  
Recurrences must be proven and documented by biopsy.  
A biopsy will be performed at screening and when indicated by direct visualization at other visits 
for purposes of staging and grading.   
The laboratory results from pathology specimens (samples taken from re-TUR of tumors) will be 
reviewed by the study investigator. These laboratory results will be provided to the investigator 
from the certified and/or accredited laboratory local to the site, where the samples were 
processed.  If there is no certified and/or accredited laboratory on site, the specimen may be 
shipped to another agreed upon certified and/or accredited laboratory for analysis and reporting 
of results to the study investigator.  There is no central laboratory review and/or evaluation 
requirement in this study.  For these efficacy analyses, recurrence will be considered biopsy 
proven and/or sufficiently documented following a local investigative pathology review that 
deems the specimen as positive.   
In the case where a patient consistently has positive cystoscopy or cytology results (3 or 
more) but repeated negative biopsy, the patient will not be considered a treatment failure for the 
EFS analyses. 
11.3 
Safety Variables 
The safety endpoint is occurrence of AEs according to CTCAE version 5.0, regardless of 
relationship to study medication. 
11.3.1 
Clinical Laboratory 
Standard clinical chemistry, hematology, and urinalysis assessments will be conducted 
periodically during the study at the hospital facilities.  Abnormalities that develop after the start 
of study medication and abnormalities present at baseline, but which worsen by at least 1 
CTCAE grade on study will be considered AEs when clinically significant.  Investigator 
discretion is allowed in determination of AEs, and investigators will assess grade, severity, and 
causality of any abnormalities considered AEs. 
11.3.2 
Adverse Events 
11.3.2.1 
Adverse Events and Serious Adverse Events 
An AE is any untoward medical occurrence in a subject participating in a clinical trial. An AE 
can be any unfavorable and unintended sign, symptom, or disease temporally associated with the 


Protocol Number: BC-819-18-204 (version 1.4) 
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Date of protocol: 24 Sep 2018 
 
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use of the study medication, whether or not considered related to the study medication. AEs will 
be collected from the time a patient signs the ICF until 30 days after the final visit.  AEs 
occurring prior to the start of treatment will be recorded in the eCRF and shown in listings but 
not in tables of AEs.  Only TEAEs (ie, those AEs that begin or worsen in severity after the start 
of treatment) will be tabulated in the AE tables and discussed in the clinical study report. 
Pre-existing, known clinically significant conditions observed at screening should be recorded as 
medical history.  Worsening of a pre-existing condition by at least 1 grade per CTCAE 
version 5.0 should be recorded as an AE. 
The definition of AEs also includes accidental injuries, reasons for any change in medication 
(drug and/or dose) other than planned titration, reasons for admission to a hospital, or reasons for 
surgical procedures (unless for minor elective surgery for a pre-existing condition). It also 
includes AEs commonly observed and AEs anticipated based on the pharmacological effect of 
the study medication.  All new laboratory abnormalities and baseline abnormalities worsening by 
at least 1 CTCAE grade must be recorded as an AE when clinically significant.  
A TEAE is any AE occurring after start of study medication or pre-existing medical 
condition that worsens in intensity after start of study medication.  
AEs should be recorded as diagnoses, if available. If not available, separate sign(s) and 
symptom(s) are recorded. One diagnosis/symptom should be entered per record.  
Note that death is not an event; however, the cause of death is. An exception is the event of 
sudden death of unknown cause. Note that hospitalization is not an event; however, the reason 
for hospitalization is. Procedures are not events; however, the reasons for conducting the 
procedures are. In general, only the reason for conducting the procedure will be captured as an 
AE. If deemed necessary by the investigator, a procedure can be captured along with the reason 
for conducting the procedure. 
An overdose or medication error is not an AE unless it is temporally associated with an 
unfavorable or unintended sign or symptom.   
Each AE is to be classified by the investigator as serious or non-serious.  An SAE is any 
untoward medical occurrence or effect that occurs at any dose which:  
• Results in death 
• Is life-threatening (ie, an immediate risk of death) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is associated with a congenital anomaly/birth defect 
• Is an important medical event 


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An AE caused by an overdose or medication error is considered serious if a criterion listed in the 
definition above is fulfilled. 
Important AEs that may not result in death, may not be life-threatening, or do not require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject’s safety or may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
SAEs also include any other event that the investigator or sponsor judges to be serious or which 
is defined as serious by the regulatory agency. 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study patient using concise medical terminology.  In addition, each study patient will be 
questioned about AEs.  The question asked will be “Since you began taking the study 
medication, have you had any health problems?” 
11.3.2.2 
Procedures for Assessing, Recording, and Reporting Adverse Events and Serious 
Adverse Events 
Throughout the study, the investigator will closely monitor each patient for evidence of drug 
intolerance and for the development of clinical or laboratory evidence of AEs.  All AEs 
(expected or unexpected) which occur during the course of the study, whether observed by the 
investigator or by the patient, and whether or not thought to be drug-related, will be reported and 
followed until resolution or until they become stable. 
The description of the AE will include description of event, start date, stop date, intensity, if it 
was serious, relationship to test drug, change in test drug dosage, if the patient died, and if 
treatment was required. 
AEs will be graded according to CTCAE version 5.0.  A copy of the terminology can be 
found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R 
eference_8.5x11.pdf 
For AEs not included in the CTCAE version 5.0, the following criteria will apply: 
Grade  
Description 
1 
Mild 
2 
Moderate   
3
Severe   
4
Life-threatening or disabling 
5
Fatal 
AEs will be coded, grouped, and tabulated by Medical Dictionary for Regulatory Activities 
(MedDRA) preferred terms (PTs) according to body system organ class (SOC).  Events will be 
coded into 1 of the following 5 causality categories: 


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Category 
Definition 
Definitely 
This category applies when, after careful medical consideration, there 
is almost no consideration of other causation. 
Probably 
There is a clinically plausible time sequence between onset of the AE 
and study treatment administration.  The AE is unlikely to be caused 
by a concurrent and/or underlying illness, other drugs, or procedures.  
If applicable the AE follows a clinically consistent resolution patter 
upon withdrawal of study drug.   
Possibly 
There is a clinically plausible time sequence between onset of the AE 
and study treatment administration, but the AE could also have been 
caused by the concurrent/underlying illness, other drugs, or 
procedures.  “Possible” should be used when study treatment 
administration is one of several biologically plausible causes of the 
AE. 
Unlikely 
The AE is most likely due to a non-study-treatment-related cause.  
However, association with the study treatment cannot be completely 
ruled out. 
Not related 
Another cause of the AE is most plausible, and a clinically plausible 
temporal sequence is inconsistent with the onset of the AE and study 
treatment administration and/or a causal relationship is considered 
biologically implausible. 
AEs with the causality assessed as unlikely and not related are categorized as not related to study 
medication for regulatory reporting.  Investigators will assess events for relationship to study 
medication (BC-819) and independently to study procedures (eg, catheterization for direct 
visualization or administration of medicine).  Investigators may assess an event as possibly 
related to more than 1 cause. 
All SAEs must be reported immediately (no more than 24 hours after becoming aware of 
the event).  The investigator must complete the initial SAE Report Form and fax/e-mail it within 
24 hours according to the SAE Report Form instructions. Any SAES occurring within 30 days 
following study discontinuation must also be reported.  The sponsor medical monitor or delegate 
is responsible for providing the sponsor’s assessment of causality and expectedness that will be 


Protocol Number: BC-819-18-204 (version 1.4) 
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Date of protocol: 24 Sep 2018 
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considered when determining if the event qualifies as a serious unexpected suspected adverse 
reaction (SUSAR) requiring expedited reporting to regulatory authorities.  
Sponsor Medical Monitor:  
Dr. Frank Haluska 
E-mail: frank.haluska@anchiano.com
Table 11.1 
Contact Research Organization Contact Information 
SAE Reporting Fax Number and Email Address 
Fax Number 
+1 877 464 7787
Email Address 
INCDrugsafety@INCResearch.com 


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Date of protocol: 24 Sep 2018 
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12.
STUDY PROCEDURES AND FLOWCHARTS
The administration of BC-819 is separated into 2 phases, the induction phase and the 
maintenance phase. 
During the induction phase, eligible patients will receive BC-819 once per week for 
10 consecutive weeks.  The flow chart for the induction phase is Table 12.1. 
During the maintenance phase, patients will transition to once every 3 weeks administration of 
BC-819 and will be evaluated every 12 weeks by cystoscopy for staging of response in order to 
determine continued participation.  The urine cytology and cystoscopy must be completed within 
14 days prior to the next administration of BC-819 and fully evaluated before initiating the 
treatment. The flow charts for the maintenance phase are Table 12.2 and Table 12.3. 
In each of the the study flow charts, a study week is defined as 7 days.  A description of each 
procedure is in Section 12.1.  End of study procedures are required within 4 weeks of leaving 
the study.  


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Table 12.1 
Induction Phase 
Visit 
Screening 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Day 
≤42 days 
before V1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
Baseline only 
procedures 
X 
Interim physical 
examination including 
ECOG performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete blood count 
and biochemical 
profile 
X 
Urine sample for 
urinalysis (routine and 
microscopic) 
X 
Urine sample for 
culture and sensitivity 
X 
Urine sample for 
cytology
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biopsy 
X 
Cystoscopy 
X 
TUR/re-TUR 
X 
QOL assessment 
X 
Administration of BC-
819 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Detailed descriptions of procedures and timing are in Section 12.1. 
Abbreviations: BC-819 = recombinant DNA plasmid complexed with polyethylenimine; ECOG = Eastern 
Cooperative Oncology Group; QOL = quality of life; re-TUR = repeat transurethral resection; TUR = transurethral 
resection; V = visit. 


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Table 12.2 
Maintenance Treatment Through Visit 23 (Week 48) 
Visit 
V11 
V12 V13 
V14 V15 
V16 
V17 V18 
V19 
V20 
V21 
V22 
V23 
Week 
12 
Day 
84 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48 
Interim physical 
examination 
including 
ECOG 
performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete blood 
count and 
biochemical 
profile 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Urine sample 
for urinalysis 
(routine and 
microscopic) 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Urine sample 
for culture and 
sensitivity 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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Maintenance Treatment Through Visit 23 (Week 48) 
Visit 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
Week 
12 
Day 
84 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48 
Mandatory 
response 
assessment for 
patients with 
CIS  
X 
 
 
 
Xa 
 
 
 
Xa 
 
 
 
Xa 
Urine sample for 
cytology (must 
be completed 
within 14 days 
prior to BC-819 
administration) 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Cystoscopy 
(must be 
completed 
within 14 days 
prior to BC-819 
administration)  
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
TUR/re-
TUR/biopsy as 
clinically 
indicated 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
QOL assessment 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Administration 
of BC-819 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Mandatory in patients who have not previously achieved a CR in their baseline CIS. 
Detailed descriptions of procedures and timing are in Section 12.1. 
Abbreviations: BC-819 = recombinant DNA plasmid complexed with polyethylenimine; CIS = carcinoma in situ; 
ECOG = Eastern Cooperative Oncology Group; QOL = quality of life; re-TUR = repeat transurethral resection; 
TUR = transurethral resection; V = visit. 
 
 
 


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Table 12.3 
Maintenance Treatment Through Visit 39 (Week 96) 
Detailed descriptions of procedures and timing are in Section 12.1. 
Abbreviations: BC-819 = recombinant DNA plasmid complexed with polyethylenimine; ECOG = Eastern 
Cooperative Oncology Group; EOS = end of study; re-TUR = repeat transurethral resection; TUR = transurethral 
resection; V = visit. 
Visit 
V24 V25 V26 V27 V28 V29 V30 V31 V32 V33 V34 V35 
V36 
V37 
V38 
V39/EOS 
Week 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
81 
84 
87 
90 
93 
96 
Interim 
physical 
examination 
including 
ECOG 
performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete 
blood count 
and 
biochemical 
profile 
X 
X 
Urine sample 
for urinalysis 
(routine and 
microscopic) 
X 
X 
Urine sample 
for culture and 
sensitivity 
X 
X 
Adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine sample 
for cytology 
(must be 
completed 
within 14 days 
prior to BC-
819 
administration)  
X 
X 
X 
X 
Cystoscopy 
(must be 
completed 
within 14 days 
prior to BC-
819 
administration)  
X 
X 
X 
X 
TUR/re-
TUR/biopsy as 
clinically 
indicated 
X 
X 
X 
X 
Administration 
of BC-819 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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12.1 
Description of Study Procedures 
The following procedures will be performed at the times noted in Table 12.1, Table 12.2, and 
Table 12.3.     
Baseline tests for evaluating eligibility will include the following:   
Informed consent:  All patients must sign the ICF.  Consent by a guardian is not 
acceptable unless the patient is unable to sign because of a physical problem with a hand 
or arm.  In that case, the patient must give verbal consent, which must be witnessed by an 
observer not directly involved in the study.  Patients who are not mentally competent to 
consent on their own are not permitted to participate in the study. The consent process 
must be properly documented in the source data. 
Medical History and Physical Examination:  Full medical history, including details of 
bladder cancer diagnosis, treatment and course, and physical examination during 
screening; directed physical examination of pertinent systems and interim history at other 
visits.  Patients will be weighed at screening, at the start of maintenance therapy visit, and 
at EOS; weight is to be recorded in kilograms. Height will be collected only at baseline 
physical examination. 
Electrocardiogram: a 12-lead electrocardiogram (ECG) will be performed at baseline 
for patients with a history or symptoms of cardiac or respiratory abnormality 12-lead if 
not performed within 1 month of study entry.  Results from an ECG performed before 
study entry must be available for review by the investigator or his/her designee; a report 
alone is not adequate. 
Chest X-Ray: Posterior-anterior and lateral chest x-ray, will be performed at baseline if 
not performed within 6 months before study entry.  Results from a chest x-ray performed 
before study entry must be available for review by the investigator or his/her designee; a 
report alone is not adequate. 
Urine Pregnancy Test: For women of childbearing potential only.  Women who are at 
least 3 months past surgical sterilization and those with no menstruation for at least 
12 months prior to entering the study are no longer considered to be of 
childbearing potential. 
Interim Physical Examination:  Examination of pertinent systems (ie, abdomen, back, and 
systems about which patient notes symptoms currently or at previous visit). Weight is to be 
recorded in kilograms at the start of maintenance therapy visit and at EOS. 
In conjunction with the physical examination, ECOG performance status will be collected at 
screening and at each study visit. 


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Table 12.4 
Eastern Cooperative Oncology Group Performance Status:  Scored 0 
(Normal Function) through 5 (Dead) 
ECOG PERFORMANCE STATUSa 
Grade 
ECOG 
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, eg, light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
a Oken et al. 1982. 
Vital Signs:  Pulse, respiratory rate, systolic and diastolic blood pressure, and temperature 
(in °C) will be recorded at all visits.  At treatment visits, vital signs should be recorded within 30 
minutes prior to starting treatment.   
Complete Blood Count/Biochemical Profile:  Complete blood count includes hemoglobin, 
total red cell count, total white blood cell (WBC) count, absolute values for individual WBC 
types, and platelet count.   
Biochemical profile will include, at a minimum, albumin, alkaline phosphatase, alanine 
aminotransferase, aspartate aminotransferase, bicarbonate, (total) bilirubin, blood urea nitrogen, 
calcium, chloride, creatinine, glucose, potassium, sodium, and total protein. 
Urinalysis:  At visit indicated, urinalysis will include the following:   
Routine:  blood, leukocytes, glucose, ketones, nitrites, pH, protein, and specific gravity 
Microscopic:   WBC, red blood cells, bacteria, epithelial cells, crystals (with type 
identified), and mucus 
Urine for Culture and Sensitivity: A urine sample will be collected for culture and sensitivity 
analysis at each visit indicated. 
Urine cytology:  The urine sample for cytology testing should be collected and analysed within 
14 days prior to scheduled treatment administration. 
Adverse Events:  Patients will be questioned regarding the occurrence or resolution of AEs.  
Details regarding collection and assessment of AEs are given in Section 11.3.2 of this protocol. 
Prior and concomitant medications: At baseline, a complete history of all treatment for 
bladder cancer, as well as all medications (both prescription and over the counter) should be 
recorded, including medication prescribed and over the counter and taken within 30 days before 
the screening visit, which will be recorded in the eCRF.  During the study, all medications, both 
prescription and over the counter, are to be recorded in the eCRF.  Indications for each 
medication should be collected, including whether the medication was taken prophylactically or 
therapeutically.   Complete dosing information (dosage and actual number of doses taken each 
day) for all medications taken during the study are to be recorded. 


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Biopsy:  Biopsy is required at baseline.  Otherwise, biopsy is only needed if either cystoscopy or 
cytology result is positive.  At baseline, site-directed mapping biopsies of normal appearing 
mucosa and any suspicious flat or papillary lesions must be performed.  A sample of the resected 
tumors should be made available for local pathology review and study documentation. 
Cystoscopy: Cystoscopy will be performed at the predetermined visits as indicated in the study 
schedules (Table 12.1, Table 12.2, and Table 12.3) with a consistent imaging technique when 
possible. Enhanced imaging (eg, blue-light or narrow band) is preferred when available.  
Cystoscopy should be performed within 14 days prior to scheduled treatment administration.  
All interior surfaces of the bladder will be examined systematically, and observations will be 
recorded. Any suspicious lesions viewed during cystoscopy should be clearly indicated on a 
bladder diagram attached to the source document and numbered. Any biopsy specimens taken 
during cystoscopy should be immediately fixed in formalin, identified by patient’s name, 
identification code, specimen number, and date (in accordance with the number assigned on the 
bladder diagram) and submitted for histopathology processing and evaluation at the local 
hospital pathology laboratory.  
A complete description of visual findings must be documented in the eCRF.  Should recurrent 
papillary tumors (of any stage or grade) or new CIS lesions be visualized in cystoscopy, a re-
TUR procedure is indicated to resect all visible papillary tumors and fulgurate all CIS lesions 
that did not clear when indicated. All resected specimens are to be examined for exclusion of 
T2 or muscle invasive disease. 
Transurethral Resection: Transurethral resection or repeat of previous TUR should be done as 
indicated in the study schedules by direct visualization. 
Quality of Life Questionnaires Quality of life will be assessed via the EORTC QLQ-C30 (a 
general questionnaire for cancer) and the QLQ-NMIBC24 (a specific questionnaire for NMIBC 
disease) for all patients according to the study procedures flow charts (Table 12.1, Table 12.2, 
and Table 12.3).  The results will be recorded in the eCRF. 
Administration of BC-819:  Study treatment will be administered as described in Section 9.4 of 
the protocol.  The window for treatment administration should be ± 5 days during induction and 
±1 week during maintenance.  However, treatment is not to be more frequent than every 5 days 
at any time during study. 
 
 


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13. 
STATISTICAL METHODS PLANNED AND SAMPLE SIZE 
13.1 
Determination of Sample Size 
The primary endpoint of the study will be based on patients in the full analysis set (FAS) 
population.  The primary endpoint will be analyzed using a two-sided 95% CI for the CR rate in 
patients who have CIS at baseline (with or without papillary disease).   A total of 140 treated 
patients will be included in this study, and it is estimated that between 70 and 100 of these will 
have CIS.  Assuming at least 70 patients with CIS, this sample size will provide over 95% power 
to detect a difference in CR rate in CIS patients of 20% and an alternative hypothesis rate of 40% 
using an exact binomial test with a nominal 0.05 two-sided significance level.  If 100 CIS 
patients are treated, the power will be approximately 92% to detect a difference from 20% using 
an alternative hypothesis rate of 35%.  The power is higher to detect differences from rates lower 
than 20%. 
13.2 
Patient Populations 
FAS:  All patients who are enrolled in the study (ie, signed the ICF) and received at least 1 dose 
of study medication.  This population will be used for efficacy and safety analyses. 
A per-protocol efficacy analysis may be conducted based on patients who met all requirements 
for the target disease at study entry and received all the prescribed treatment without major 
protocol violations that might have a major effect on efficacy analysis.  Classes of major protocol 
deviations will be defined and documented prior to the conduct of the primary analysis. These 
will include but are not limited to significant misuse of the drug (eg, wrong dose, missed doses, 
too long a delay) and violations of target disease (eg, presence of muscle invasion on subsequent 
review).  This analysis will only be performed if a sizeable number of patients are excluded 
based on this review.  Further detail will be included in the statistical analysis plan. 
Any AEs and laboratory data generated prior to start of treatment will be included in separate 
listings from those of patients treated during the study. 
13.3 
Subject Disposition 
The number of patients who complete and who do not complete the study will be summarized. 
Reasons for patients not completing the study will be categorized as follows: 
• Adverse event:   
o Related to study medication 
o Related to study procedure 
o Unrelated to either study medication or procedure 
• For patients with CIS at baseline, failure to clear CIS lesions by the 12-week cystoscopy. 
These patients can be followed by cystoscopy in the study until they begin an alternative 
treatment or undergo cystectomy 
• Recurrence:  recurrence requiring discontinuation from the study (see Section 9.6) 
• Death from any cause (with specification of cause of death) 
• Withdrawal of consent 


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• Loss to follow-up 
• Other (with specification of reason) 
The primary reason for discontinuation will be listed.  Thus, if a patient discontinues therapy 
because of an AE and subsequently dies, the reason for discontinuation will be listed as AE. 
As etiology of AEs is often uncertain, more than 1 reason for an AE resulting in discontinuation 
(eg, both BC-819 and study procedure [catheterization]) may be listed as causes, although the 
primary reason for discontinuation will be AE. 
13.4 
Demographics and Baseline Characteristics 
Demographic and pre-treatment patient characteristics, including disease parameters and 
comorbidities, will be summarized with descriptive statistics.  The descriptive statistics will 
include sample size, mean, standard deviation, median, minimum, and maximum for continuous 
variables and number and percentages for discrete variables.  No formal inferential tests will 
be performed. 
13.5 
Efficacy Analysis 
13.5.1 
Primary Efficacy Analysis 
The primary endpoint of the study is the CR rate in patients with CIS, supported by duration of 
the complete response.  
A CR in patients with CIS is defined as at least one of the following: 
• Negative cystoscopy and negative (including atypical) urine cytology 
• Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative 
cytology 
• Negative cystoscopy with malignant urine cytology if cancer is found in the upper tract or 
prostatic urethra and random bladder biopsies are negative 
The complete response in patients with CIS for this endpoint must be documented on or after the 
Week 12 response assessment and on or prior to the Week 48 assessment. The durability of the 
CRs will be described using Kaplan-Meier Plots of the duration of CR in responders.  Duration 
of complete response in patients with CIS will be calculated from the documented onset of the 
complete response to the assessment where the patient no longer meets the definition of complete 
response.  More generally, Rrecurrence is defined as the reappearance or persistence of 
high-grade disease or new high-grade disease.  Recurrence must be biopsy proven.  Persistence, 
appearance, or presence of lower grade disease will not be considered recurrence.  Sensitivity 
analyses for duration of response will be performed starting from the time the CIS lesion clears 
to time that new CIS lesions are identified, censoring patients with no CIS but other high-grade 
disease at the time of recurrence and a separate analysis looking at the time from response until 
any NMIBC is found (including low-grade disease). 
13.5.2 
Interim Analyses 
The first 35 patients in the study are to be CIS patients (with or without papillary disease).  An 
interim analysis for futility will be conducted using the response data in these patients.  If 9 or 
fewer of these first 35 patients achieve CR, the study may be stopped for futility.  If 10 or more 


Protocol Number: BC-819-18-204 (version 1.4) 
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Date of protocol: 24 Sep 2018 
 
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patients achieve a CR, then the study will continue and all patients meeting entry criteria may be 
enrolled (including those with papillary disease without CIS).  The enrollment will be paused 
after 35 patients to evaluate this data unless 10 or more responses have already been documented 
when the 35th CIS patient is enrolled. 
When the true CR rate is 40% or higher, the probability of proceeding with 10 or more CRs out 
of the first 35 patients is over 94%.  When the true CR rate is 15% or lower, the probability of 
9 or fewer responses is over 97%. 
13.5.3 
Secondary Efficacy Analyses 
The secondary efficacy endpoints include the following: 
• The incidence of EFS at 48 weeks, where EFS is defined as high-grade recurrence-free 
survival (overall population and subgroup of patients with CIS)  
• The incidence of EFS at 12, 24, 36, 72, and 96 weeks, where EFS is defined as high-
grade recurrence-free survival (overall population and subgroup of patients with CIS)  
• Time to recurrence; recurrence is defined as an EFS event  
• The incidence of PFS at 48, 72, and 96 weeks as well as time to progression estimated 
using Kaplan-Meir methods.  Progression is defined as the development of T2 or greater 
disease.  Sensitivity analyses will also be performed and will include any of the following 
as progressions: 
o An increase in stage from Ta or CIS to T1, or  
o Development of T2 or greater, or  
o Lymph node disease, or  
o Distant metastasis 
• Overall survival of patients enrolled in the study at 48, 72, and 96 weeks and survival 
time estimated using Kaplan-Meier methods 
• Changes in quality of life over time, as measured by EORTC QLQ-C30 and 
QLQ-NMIBC24 
Additionally, patients with appearance of new high-grade disease (ie, new high-grade papillary 
disease in patients with CIS only or new CIS in patients with papillary disease only) will be 
classified as treatment failures, as will patients with CIS at baseline whose CIS lesions have not 
resolved by the 12-week cystoscopy.  
Any patient without tumor in the bladder but presence of tumor in the upper urinary tract will not 
be classified as failures in these analyses and will continue study participation. 
Rates will be summarized using two-sided 95% confidence intervals (using Kaplan-Meier 
estimates incorporating censoring for PFS and overall survival and both Kaplan-Meir estimates 
and exact binomial methods for EFS).  Time to recurrence and other endpoints will be examined 
using Kaplan-Meier methods, with plots for the entire patient population, for subgroups of 
patients with papillary lesions only, and for patients with CIS (with or without papillary lesions).  
Time 0 is the time of first treatment with BC-819. 
Further sensitivity and subgroup analyses will be described in the statistical analysis plan. 


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13.5.4 
Handling of Missing Data 
All efforts will be made to avoid missing data. If, however, it does occur, it will be handled as 
follows:  
• If a visit has been missed and cytology results are available at the next visit and no 
disease is present, then the earlier visit will be counted as absence of disease.  
• In addition, the count of absence of disease will be based on visit findings, meaning that 
if a patient missed a visit and at the next visit he/she experienced a recurrence, the 
recurrence will be counted only from the day on which evidence was provided. 
Patients with CIS lesions that do not resolve by the 12-week cystoscopy will be classified as EFS 
events.  For Kaplan-Meier analyses of EFS, they will be considered to have recurred 
at 12 weeks. 
Any patient without tumor in the bladder but presence of tumor in the upper urinary tract will 
not be classified as failures in the CR and EFS analyses and will continue study participation. 
Additional subgroup analyses may be included in the statistical analysis plan. 
13.6 
Safety Analysis 
Safety will be assessed by evaluation of AEs and clinical laboratory results. 
13.6.1 
Adverse Events 
AEs will be coded to SOC and PT using MedDRA.  All AEs occurring after the patient signs the 
ICF will be recorded, but only those occurring after the start of the study treatment (TEAEs) will 
be summarized in tables.  AEs occurring between signing of the ICF and start of study 
medication will be included in separate listings from TEAEs. 
AEs will be summarized by incidence of AEs (the number of patients reporting at least 1 episode 
of a specific AE), incidence of AEs by severity within body system, incidence of AEs by 
attribution within body system, and incidence of AEs causing withdrawal and incidence of 
SAEs.  Regarding severity and attribution summaries, the most extreme outcome (highest 
severity and closest to study drug-related) will be used for those patients who experience the 
same AE on more than 1 occasion. 
In addition to standard MedDRA SOC and PT tables of AEs, a composite class of urinary tract‒
related AEs will also be created and the incidence and severity of AEs in this composite class 
tabulated.  SOC and PTs for urinary tract‒related AEs are shown in Table 13.1. 


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Table 13.1 
Urinary Tract‒Related Adverse Events 
System Organ Class 
Preferred Term 
Infections and infestations 
Urinary tract infection 
Urosepsis 
Investigations 
Blood creatinine increased 
Renal and urinary disorders 
Any 
Written narratives will be provided for all serious, unexpected or other significant AEs that are 
judged to be of special interest because of their clinical importance. 
13.6.2 
Clinical Laboratory 
Clinical laboratory results will be summarized with descriptive statistics at baseline, each study 
time point, and with shifts from baseline for key variables.  Units of measurement for laboratory 
results will be centrally converted, when necessary, to a uniform standard for presentation of 
results across all participating study sites (eg, via the eCRF software).  Particular attention will 
be paid to urinary findings. 
Laboratory abnormalities that develop after the start of study medication and abnormalities 
present at baseline, but which worsen by at least 1 CTCAE grade on study will be considered 
AEs when clinically significant.  Investigator discretion is allowed in determination of AEs, and 
investigators will assess grade, severity, and causality of any abnormalities considered AEs. 
 
 


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14. 
DATA QUALITY 
14.1 
Source Data and Records 
Source data/records contain all the information that is necessary for the reconstruction and 
evaluation of the study. Source data/records are 1) original records; 2) certified copies of original 
records; 3) observations; 4) laboratory reports; and 5) data sheets, whether recorded in hard copy 
or electronic medical records. Source data/records are to be kept within the control of the 
investigator until the end of the regulatory retention period. The investigator will permit study-
related monitoring, audit(s), IRB review(s) and regulatory inspection(s), with direct access to all 
the required source records. 
14.2 
Electronic Data Capture 
Clinical study data will be transcribed from source records by the investigator or a designee into 
a validated, 21 Code of Federal Regulations Part 11 compliant, Internet-based electronic data 
capture (EDC) system.  Data entry into the EDC system should be completed in a timely manner 
following completion of each patient visit. 
The investigator and staff will be trained to use the EDC system before enrollment of the first 
patient.  A list of the status of each user, including an audit trail of status changes, will 
be maintained.  
At the end of the study, the completed online eCRF must be reviewed and signed electronically 
by the investigator named in the study protocol or by a designated sub-investigator authorized to 
sign.  A certification must be obtained from all authorized persons to sign electronically, 
indicating that their electronic signature is equivalent to their hand-written signature.  In order to 
sign electronically, the signer must log in with his/her username and password and re-enter 
his/her password on the page(s) requiring a signature(s).  
14.3 
 Data Management 
A Data Management Plan will be created to specifically identify how data management will be 
performed for the study.   
Queries will be handled within the EDC application.  The monitors and data managers (DMs) 
will be the only persons who can generate a query.  Under direction of the investigator, the site 
coordinator will address the query.  If the query is because of a data entry error, the coordinator 
can immediately make the corrections in the applicable eCRF pages.  If the query needs 
clarification, the coordinator will contact the investigator for resolution.  The coordinator will 
then enter the correct value or submit an answer to the query without modifying the data.  The 
assigned data management staff and/or monitor will then review the corrected eCRF pages 
and/or answer.  If the data are changed correctly or the answer is acceptable, data management or 
monitor will close the query.  If the answer is not acceptable, the monitor will submit an 
additional query for clarification.  All changes to the database require a “Reason for Change” and 
are subject to an audit trail.  The audit trails identify the changed data, reason(s) for change, who 
changed the data and the time, and date of the change. 
Centralized monitoring will be performed at an agreed-upon frequency, as defined in the Clinical 
Monitoring Plan.  Meetings with the clinical research and DM teams are held to review and 


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discuss data quality and data management issues and minutes of meetings maintained.  When 
necessary, the Clinical Monitoring Plan will be revised and corrective actions implemented. 
14.4 
Study Master File 
The Study Master File for both the investigator and the sponsor will be maintained in either hard 
copy or electronically using 21 Code of Federal Regulations Part 11 compliant software.   
14.5 
Record Retention  
All study records will be retained for a period of time as defined by the regulatory authority for 
the country in which the investigation is conducted.  Generally, this means at least 2 years after 
the date on which the drug is approved by the regulatory authority for marketing for the 
indication studied in the clinical trial.  In other situations (eg, where the investigation is not in 
support of or as part of an application for a research or marketing permit), a period of 2 years 
after the date on which the entire clinical program is completed, terminated or discontinued, or 
the investigational application under which the investigation is being conducted is terminated or 
withdrawn by the regulatory authorities. 
In the event the investigator retires, relocates, or for any other reason withdraws from the 
responsibility for maintaining records for the period of time required, custody of the records may 
be transferred to any other person who will accept responsibility for the records.  Notice of such 
a transfer must be given in writing to the sponsor.  The investigator must contact the sponsor 
before disposal of any records related to this study.  
14.6 
Confidentiality of Patient Data 
The investigator will ensure that the confidentiality of the patients’ data will be preserved.  In the 
eCRF or any other documents submitted to the sponsor, the patients will not be identified by 
their names, but by a unique identifier number in the study.  The investigator will maintain 
documents not meant for submission to the sponsor (eg, the confidential patient identification 
code and the signed ICFs) in strict confidence.  All data are subject to monitoring, audits, 
and inspection. 
14.7 
Monitoring Plan 
The Clinical Monitoring Plan identifies the monitoring schedule and the rationale for the 
frequency and type of monitoring visits.  A detailed Clinical Monitoring Plan will be developed 
by the sponsor and the identified contract research organization. 
14.8 
Site Visits 
Sites will undergo qualification, initiation, monitoring, and close-out visits per INC Research 
standard operating procedure (SOP).  
14.9 
Investigational Medicinal Product  
Monitors will verify that the investigator maintains accurate and adequate records, including 
dates of treatment, duration of treatment, and appropriate follow-up, and that the source 
documents are being maintained.  Monitors will perform IMP accountability and verify storage 
conditions of the IMP (secure location, temperature logs, etc) in accordance with manufacturers’ 


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instructions.  Monitors will verify that sites have an adequate supply for ongoing and 
new patients.  
During the course of the study, the monitor is responsible for the accountability and 
reconciliation of the IMP.  To assist with this, the following documents will need to be 
reviewed by the monitor, as appropriate: 
• IMP Shipment Request Form  
• IMP Receipt  
• The monitor will return the IMP as instructed by the sponsor at the completion of the 
study at the site.  The monitor will need to do the following: 
o Complete IMP Return Forms (if any) 
o Record all return shipping information 
14.10 Laboratory Samples and Analysis 
The laboratory samples will be collected and analyzed at a laboratory that is local to the site.   
Monitors will review local laboratory documentation to ensure that the relevant laboratory 
certifications and/or accreditations are current.  Additionally, monitors will verify that the local 
laboratory maintains accurate and adequate records of laboratory sample storage, temperature 
logs, and periodic laboratory equipment calibration events. 
 
 


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15. QUALITY CONTROL AND QUALITY ASSURANCE 
The sponsor and designated clinical research organizations maintain a quality assurance system 
with written SOPs to ensure that clinical trials are conducted, and data are generated, 
documented, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirements.  
15.1 
Audits and Inspections 
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the Sponsor Quality Assurance or its 
designees or to regulatory authority inspectors after appropriate notification. The verification of 
the eCRF data must be by direct inspection of source documents. These audits or inspections 
may take place at any time during or after the study and are based on the national regulations as 
well as International Council for Harmonisation guidelines.  
15.2 
Laboratory Quality Standards 
Laboratory tests or evaluations described in this protocol will be conducted in accordance with 
quality laboratory standards as described in the SOPs of the central laboratories. 
 
 


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16. 
REPORTING AND PUBLICATION 
16.1 
Confidentiality of Study Data 
Any information relating to the study product or the study, including any data and results from 
the study, will be the exclusive property of the sponsor. The investigator and any other persons 
involved in the study will protect the confidentiality of this proprietary information belonging to 
Anchiano Therapeutics Israel Ltd. 
16.2 
Publication Policy 
Anchiano Therapeutics Israel Ltd. agrees to make the report of the multicenter study results 
available to all study investigators.  The Anchiano Therapeutics Israel Ltd. database is the 
official data record. A paper will be prepared based on the report and published by all 
investigators as a group, identifying the lead investigator and sponsor.  Notwithstanding this, 
each investigator has the right to publish his/her “contribution to the study” at any relevant venue 
as long as the sponsor (Anchiano Therapeutics Israel Ltd.) has been notified and received an 
advance copy within 30 days of the publication for review.  Anchiano Therapeutics Israel Ltd. 
will have 30 days to review any proposed publication of the data for accuracy and 
proprietary information. 
16.3 
Study Registration 
This study will be registered on www.clinicaltrials.gov or another publicly accessible database 
before the enrollment of the first patient.  Results from the study will be posted on the registry in 
accordance with local laws and regulations. 
 
 


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17. 
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Lerner SP, Dinney C, Kamat A, Bivalacqua TJ, Nielsen M, O’Donnell M, et al. Clarification of 
bladder cancer disease states following treatment of patients with intravesical BCG. 
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promotes tumour metastasis. Biochem Biophys Acta. 2014;1843(7):1414-1426. 
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gene in DNA based therapy of bladder cancer. Gene Ther Mol Biol. 2004;8:181-192. 
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SAP_001.pdf: 
Statistical Analysis Plan for Phase I/II Oncology Studies 
Sponsor: Anchiano Therapeutics Israel Ltd., Protocol No.: BC-819-18-204 
 
 
This document is confidential. 
SAP Version: Draft 0.3, 16JUN2019 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 3 of 34 
Filing requirement: TMF 
Statistical Analysis Plan 
 
Sponsor Name: Anchiano Therapeutics Israel Ltd 
 
Protocol Number: BC-819-18-204 
 
Protocol Title: A Phase 2 Study of BC-819 in Patients with Non-Muscle Invasive Bladder Cancer Whose 
Disease is Unresponsive to Bacillus Calmette-Guerin 
 
Protocol Version and Date: Version 1.4, 24-Sep-2018 
 
Syneos Health Project Code: 1010798B 
 
Author(s) : Alex Hsi, Senior Biostatistician 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Anchiano Therapeutics Israel Ltd. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Anchiano Therapeutics 
Israel Ltd. However, this document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the condition that 
they are requested to keep it confidential. In the event of an actual or suspected breach of this obligation, 
Syneos Health should be notified promptly. 
 


Statistical Analysis Plan for Phase I/II Oncology Studies 
Sponsor: Anchiano Therapeutics Israel Ltd., Protocol No.: BC-819-18-204 
 
 
This document is confidential. 
SAP Version: Draft 0.3, 16JUN2019 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 3 of 34 
Filing requirement: TMF 
Table Of Contents 
List of Abbreviations and Definition of Terms .............................................................................. 4 
1. 
Introduction ........................................................................................................................ 5 
2. 
Study Objectives ................................................................................................................ 7 
2.1 
Primary Objectives ............................................................................................... 7 
2.2 
Secondary Objectives .......................................................................................... 7 
3. 
Study Design ...................................................................................................................... 8 
3.1 
Overall Study Design ............................................................................................ 8 
4. 
Schedule of Assessments .................................................................................................. 9 
5. 
Endpoints ......................................................................................................................... 15 
5.1 
Efficacy Endpoints.............................................................................................. 15 
5.1.1 
Primary Efficacy Endpoint .................................................................................... 15 
5.1.2 
Secondary Efficacy Endpoints ............................................................................. 15 
5.2 
Safety Endpoints ................................................................................................ 16 
6. 
Analysis Populations ........................................................................................................ 17 
7. 
Statistical Methodology..................................................................................................... 18 
7.1 
Statistical and Analytical Considerations ......................................................... 18 
7.1.1 
Statistical Methods ............................................................................................... 18 
7.1.2 
Visit Windows ....................................................................................................... 18 
7.1.3 
Handling of Missing Data ..................................................................................... 18 
7.1.4 
Pooling of Investigative Sites ............................................................................... 20 
7.1.5 
Determination of Sample Size ............................................................................. 20 
7.2 
Patient Characteristics ....................................................................................... 20 
7.2.1 
Patient Disposition ............................................................................................... 20 
7.2.2 
Protocol Deviations .............................................................................................. 21 
7.2.3 
Demographic and Other Baseline Characteristics ............................................... 21 
7.2.4 
Treatment Exposure and Compliance ................................................................. 21 
7.2.5 
Prior Cancer Therapies ........................................................................................ 22 
7.2.6 
Prior and Concomitant Medications  .................................................................... 23 
7.2.7 
Medical Histories .................................................................................................. 23 
7.3 
Efficacy Analysis ................................................................................................ 23 
7.3.1 
Primary Efficacy Analysis ..................................................................................... 23 
7.3.2 
Secondary Efficacy Analyses ............................................................................... 24 
7.4 
Safety Analysis ................................................................................................... 26 
7.4.1 
Adverse Events .................................................................................................... 26 


Statistical Analysis Plan for Phase I/II Oncology Studies 
Sponsor: Anchiano Therapeutics Israel Ltd., Protocol No.: BC-819-18-204 
 
 
This document is confidential. 
SAP Version: Draft 0.3, 16JUN2019 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 3 of 34 
Filing requirement: TMF 
7.4.2 
Physical Examination ........................................................................................... 27 
7.4.3 
Vital Signs ............................................................................................................ 27 
7.4.4 
Electrocardiogram ................................................................................................ 28 
7.4.5 
Laboratory Parameters ........................................................................................ 28 
7.4.6 
Evaluation of Performance Status ....................................................................... 28 
7.5 
Interim Analysis .................................................................................................. 29 
7.6 
Subgroup Analysis ............................................................................................. 29 
7.7 
Changes to Methods Planned in the Protocol .................................................. 30 
8. 
Tables, Listings, And Figures ........................................................................................... 31 
8.1 
Programming Guidelines ................................................................................... 31 
8.1.1 
Format of Output .................................................................................................. 31 
8.1.2 
Format of Data ..................................................................................................... 31 
8.2 
Table of Contents for Tables, Listings and Figures ......................................... 32 
8.2.1 
List of Tables ........................................................................................................ 32 
8.2.2 
List of Listings ...................................................................................................... 32 
8.2.3 
List of Figures ....................................................................................................... 32 
9. 
References ....................................................................................................................... 33 
10. 
Appendices ...................................................................................................................... 34 
10.1 
Table of Contents of Interim Analysis ............................................................... 34 
 


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List of Abbreviations and Definition of Terms 
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
BCG 
bacillus Calmette-Guerin 
CIS 
carcinoma in situ 
CR 
complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DTA 
diphtheria toxin A 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EFS 
event-free survival 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire 
FAS 
full analysis set 
FDA 
US Food and Drug Administration 
MedDRA 
Medical Dictionary for Regulatory Activities 
NMIBC 
non-muscle invasive bladder cancer 
PFS 
progression-free survival 
PT 
preferred term 
QLQ-NMIBC24 
Non-Muscle Invasive Bladder Cancer Questionnaire 
re-TUR 
repeat transurethral resection 
SAE 
serious adverse event 
SOC 
system organ class  
TEAE 
treatment-emergent adverse event 
TUR 
transurethral resection 
WBC 
white blood cell 
WHO 
World Health Organization 


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1. 
Introduction 
Bladder cancer is a common illness, the ninth most common cancer worldwide and the fourth most 
common cancer in men in the United States. An estimated 79,030 new cases of bladder cancer are 
expected to occur in the United States in 2017. Bladder cancer incidence is about 4 times higher in men 
than in women and almost 2 times higher in Caucasian men than in African-American men (American 
Cancer Society 2016). 
 
Most bladder cancers are transitional cell carcinomas, and most are superficial (ie, do not penetrate the 
muscularis layer), hence the term non-muscle invasive bladder cancer (NMIBC). The estimated 
proportion of patients with bladder cancer that is non-muscle invasive in the US is 70% to 80% (Lamm 
2002; Madeb et al. 2009; Shelley et al. 2010). Of these new NMIBC cases, approximately 70% are Ta 
(confined to bladder epithelium), 20% are T1 lesions (invasion of lamina propria), and 10% are Tis 
disease (carcinoma in situ [CIS] lesions). As much as 80% of patients with Ta disease can be expected to 
experience disease recurrence, and up to 45% of patients with T1 or CIS lesions will experience disease 
progression without treatment (van Rhijn et al. 2009). 
 
The primary treatment approach to NMIBC is surgical therapy of resectable disease coupled with 
adjuvant therapy. Intravesical bacillus Calmette-Guerin (BCG) instillation has been the mainstay of 
treatment of intermediate- and high-risk NMIBC for several decades (Lamm 2002). t is used as an 
adjuvant after transurethral resection (TUR) of papillary carcinomas and for the treatment of CIS lesions. 
BCG has been shown to decrease progression as well as recurrence (Sylvester et al. 2002). Several 
chemotherapeutic agents, including mitomycin C, have also shown efficacy in certain groups of patients 
with NMIBC (Shelley et al. 2010). However, recurrence is the norm, with approximately 60% to 70% of 
patients experiencing recurrences after initial treatment and 25% progressing to invasive disease 
(Morgan et al. 2011). Hence, there is an established unmet medical need and new treatment agents are 
needed. 
 
BC-819 has been designed to exploit the specificity of H19 activation to express diphtheria toxin A (DTA) 
in bladder cancer cells. BC-819 DS is a double-stranded DNA plasmid 4560 base pairs in length. Two 
clinical studies (one Phase 1 study and one Phase 2 study) of the intravesical administration of BC-819 
as a single agent have been completed to date in patients with NMIBC. Additionally, a Phase 2 
combination therapy study of the administration of BC-819 and BCG has also been completed. 
 
The population for this study is patients with high-risk NMIBC whose disease is unresponsive to BCG. 
This is a patient population for which treatment options are limited and outcomes are usually poor. In this 
setting, a single-arm Phase 2 clinical study with complete response rate as the primary endpoint can 
provide primary evidence of effectiveness to support a marketing application. 
 
The primary endpoint of this study will be to determine in patients with baseline CIS, the proportion of 
patients that experiences a complete response (CR). In this study, in accordance with the US Food and 
Drug Administration (FDA) guidance, complete response is defined as negative urine cytology and no 
lesions visible on cystoscopy, negative urine cytology with biopsy proven benign or low-grade NMIBC, or 
negative cystoscopy with malignant urine cytology, if cancer is found in the upper tract or prostatic urethra 
and random bladder biopsies are negative. Additionally, the duration of the response will be determined. 
Recurrence is defined as the reappearance or persistence of high-grade disease. Recurrence must be 
biopsy proven. Persistence, appearance, or presence of lower grade disease will not be considered 


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recurrence. Additionally, patients with appearance of new high-grade disease (ie, new high-grade 
papillary disease in patients with CIS only or new CIS in patients with papillary disease only) will be 
classified as failures, as will patients with CIS at baseline whose CIS lesions have not resolved by the 12-
week cystoscopy or who have CIS or high-grade papillary disease at later timepoints. 
 
High-risk recurrences are the most important predictors of risk of tumor progression. Patients who recur 
with only low-grade recurrence will not be considered treatment failures and may continue study 
participation after standard-of-care resection of the new lesion(s), if any. Sylvester et al. (2006) developed 
a model for predicting recurrence and progression in NMIBC. In this model, which included tumor grade, 
low-grade tumors, there was a low potential for progression. Fernandez-Gomez et al. (2009) used a 
similar approach and considered a population in which all patients had been treated with BCG. These 
analyses demonstrated that high-grade tumor was a moderate risk factor for recurrence but a very strong 
risk factor for progression. Conversely, presence of low-grade tumor had little effect on progression. 
Therefore, the primary target population for this study focuses on patients with elevated risk for 
progression and comprises patients with high-risk/grade NMIBC that is BCG-unresponsive. 


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2. 
Study Objectives 
2.1 
Primary Objectives 
The primary objective is to determine, for the patients with baseline CIS: 
• 
The proportion that achieves a CR after treatment with inodiftagene vixteplasmid 
2.2 
Secondary Objectives 
The secondary objectives are to determine the: 
• 
Proportion of patients with absence of high-grade recurrent or persistent disease at 48 weeks 
(overall population and subgroup of patients with CIS) 
• 
Proportion of patients with absence of high-grade recurrent or persistent disease at 12, 24, 36, 72, 
and 96 weeks (overall population and subgroup of patients with CIS) 
• 
Time to recurrence (Kaplan-Meier plot) 
• 
Proportion of patients who are progression-free at 48, 72, and 96 weeks 
• 
Overall survival of patients enrolled in the study at 48, 72, and 96 weeks 
• 
Quality of life in patients treated with inodiftagene vixteplasmid 
• 
Assessment of safety 
 
 


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3. 
Study Design 
3.1 
Overall Study Design 
This study, BC-819-18-204 (referred to as Study 204), is a Phase 2, open-label, monotherapy, single-
arm, multicenter clinical trial of BC-819 (inodiftagene vixteplasmid) in patients with NMIBC adequately 
treated with BCG whose disease is BCG-unresponsive according to the FDA guidance (FDA 2018). 
Patients with BCG-unresponsive disease have NMIBC that is unlikely to benefit from and should not be 
treated with further intravesical BCG. 
Patients are to have recurred or progressed after adequate treatment, had BCG-unresponsive disease, 
had a TUR, and then had all papillary disease completely resected and obvious CIS disease fulgurated 
when indicated. Patients with T1 disease should undergo resection of the base of the lesion when 
possible (biopsy should contain muscle fiber). Patients must have 1 or more of the following: completely 
resected high-grade T1 disease, CIS disease, or completely resected high-grade Ta disease. There is no 
intravesical or medical standard of care for this patient population, and the usual course is radical 
cystectomy. 
A total of 140 patients who meet study entry criteria will be enrolled and treated during the approximately 
15-month enrollment period. The first 35 patients enrolled and treated must have CIS (with or without 
papillary disease). After these 35 patients are treated and 10 complete responders are documented, the 
enrollment will expand to also allow patients with papillary disease only who meet inclusion and exclusion 
criteria. It is estimate that a total of approximately 70 to 100 patients with CIS will be treated. 
All enrolled patients will enter the 10-week induction phase and begin treatment with BC-819. Treatment 
should begin within 7 days of enrollment and ≤42 days from the last TUR or biopsy. During the induction 
phase, patients will receive an intravesical instillation of BC-819 at a dose of 20 mg/50 mL aqueous 
solution once per week for 10 weeks according to the induction phase treatment 
schedule (see 


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Table 1). 
Upon completion of the induction phase, patients will continue with maintenance therapy of BC-819 every 
3 weeks beginning at Week 12 (Visit 11) and continuing for the next 84 additional weeks until the end of 
the study, defined as completion of the 96-week visit (Visit 39). 
During the study, patients will undergo repeat direct visualization (ie, cystoscopy ± biopsy and cytology) 
and re-TUR (as needed for cause) every 12 weeks during the first and second year. Patients with 
persistent CIS which does not resolve by the 12-week assessment, or at subsequent 12-week 
assessments, or who have recurrence or new evidence of CIS or high-grade papillary disease at any time 
will be discontinued and classified as nonresponders and recurrences in the primary and secondary 
endpoint analyses. Patients benefiting from treatment, with no documented high-grade recurrence or 
progression, will continue to receive maintenance therapy every three weeks. Appearance or persistence 
of lower grade tumors will not be considered as recurrence for the primary and secondary endpoint 
analyses, and patients with only low-grade tumors should continue treatment after resection and 
histological confirmation.  
 
 


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4. 
Schedule of Assessments 
The administration of BC-819 is separated into 2 phases, the induction phase and the maintenance 
phase. 
During the induction phase, eligible patients will receive BC-819 once per week for 10 consecutive weeks. 
The flow chart for the induction phase is 


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Table 1. 
During the maintenance phase, patients will transition to once every 3 weeks administration of BC-819 
and will be evaluated every 12 weeks by cystoscopy for staging of response in order to 
determine continued participation. The urine cytology and cystoscopy must be completed within 14 days 
prior to the next administration of BC-819 and fully evaluated before initiating the treatment. The flow 
charts for the maintenance phase are Table 2 and Table 3. 
 
 


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Table 1 Induction Phase 
Visit 
Screening 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Day 
≤42 days before V1  
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
Baseline only procedures 
X 
 
 
 
 
 
 
 
 
 
 
Interim physical examination including 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete blood count and biochemical 
profile 
X 
 
 
 
 
 
 
 
 
 
 
Urine sample for urinalysis (routine and 
microscopic) 
X 
 
 
 
 
 
 
 
 
 
 
Urine sample for culture and sensitivity 
X 
 
 
 
 
 
 
 
 
 
 
Urine sample for cytology 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biopsy 
X 
 
 
 
 
 
 
 
 
 
 
Cystoscopy  
X 
 
 
 
 
 
 
 
 
 
 
TUR/re-TUR 
X 
 
 
 
 
 
 
 
 
 
 
QOL assessment 
 
X 
 
 
 
 
 
 
 
 
 
Administration of BC-819 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BC-819 = recombinant DNA plasmid complexed with polyethylenimine; ECOG = Eastern Cooperative Oncology Group; QOL = quality of life; re-TUR = repeat 
transurethral resection; TUR = transurethral resection; V = visit. 
 
 


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Table 2 Maintenance Treatment Through Visit 23 (Week 48)  
Visit 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
Week 
12 Day 84 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48 
Interim physical 
examination including 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete blood count and 
biochemical profile 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Urine sample for urinalysis 
(routine and microscopic) 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Urine sample for culture 
and sensitivity 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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Maintenance Treatment Through Visit 23 (Week 48) 
Visit 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
Week 
12 Day 
84 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48 
Mandatory response 
assessment for patients 
with CIS  
X 
 
 
 
Xa 
 
 
 
Xa 
 
 
 
Xa 
Urine sample for cytology 
(must be completed within 
14 days prior to BC-819 
administration) 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Cystoscopy 
(must be completed within 
14 days prior to BC-819 
administration)  
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
TUR/re-TUR/biopsy as 
clinically indicated 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
QOL assessment 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Administration of BC-819 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Mandatory in patients who have not previously achieved a CR in their baseline CIS. 
Abbreviations: BC-819 = recombinant DNA plasmid complexed with polyethylenimine; CIS = carcinoma in situ; ECOG = Eastern Cooperative Oncology Group; QOL = quality of life; 
re-TUR = repeat transurethral resection; TUR = transurethral resection; V = visit. 
 
 


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Table 3 Maintenance Treatment Through Visit 39 (Week 96)  
Visit 
V24 
V25 
V26 
V27 
V28 
V29 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39/E
OS 
Week 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
81 
84 
87 
90 
93 
96 
Interim physical 
examination 
including ECOG 
performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete blood 
count and 
biochemical profile 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Urine sample for 
urinalysis (routine 
and microscopic) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Urine sample for 
culture and 
sensitivity 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine sample for 
cytology (must be 
completed within 
14 days prior to 
BC-819 
administration)  
 
 
 
X 
 
 
 
X 
 
 
 
X  
 
 
 
X 


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Abbreviations: BC-819 = recombinant DNA plasmid complexed with polyethylenimine; ECOG = Eastern Cooperative Oncology Group; EOS = end of study; re-TUR = repeat 
transurethral resection; TUR = transurethral resection; V = visit. 
 
 
Cystoscopy 
(must be 
completed within 
14 days prior to 
BC-819 
administration)  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
TUR/re-
TUR/biopsy as 
clinically indicated 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Administration of 
BC-819 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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5. 
Endpoints 
5.1 
Efficacy Endpoints 
5.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is, in patients with CIS at baseline, the: 
• 
Proportion that achieves a CR at any time on or after week 12  
Complete response is defined as at least one of the following: 
• 
Negative cystoscopy and negative (including atypical) urine cytology 
• 
Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative cytology 
• 
Negative cystoscopy with malignant urine cytology if cancer is found in the upper tract or prostatic 
urethra and random bladder biopsies are negative 
The complete response in patients with CIS for this endpoint must be documented on or after the Week 
12 response assessment. Duration of complete response in patients with CIS will be calculated from the 
documented onset of the complete response to the assessment where the patient no longer meets the 
definition of complete response. More generally, recurrence is defined as the reappearance or 
persistence of high-grade disease, or new high-grade disease. Recurrence must be biopsy proven. 
Persistence, appearance, or presence of lower grade disease will not be considered recurrence.  
5.1.2 Secondary Efficacy Endpoints  
The secondary efficacy endpoints include the following: 
• 
The incidence of event-free survival (EFS) at 48 weeks, where EFS is defined as high-grade 
recurrence-free survival (overall population and subgroup of patients with CIS) 
• 
The incidence of EFS at 12, 24, 36, 72, and 96 weeks, where EFS is defined as high-grade 
recurrence-free survival (overall population and subgroup of patients with CIS) 
• 
Time to recurrence; recurrence is defined as an EFS event  
• 
The incidence of PFS at 48, 72, and 96 weeks as well as time to progression estimated using 
Kaplan-Meier methods. Progression is defined as the development of T2 or greater disease. 
Sensitivity analyses will also be performed and will include any of the following as progressions: 
o 
An increase in stage from Ta or CIS to T1, or  
o 
Development of T2 or greater, or  
o 
Lymph node disease, or  
o 
Distant metastasis  
• 
Overall survival of patients enrolled in the study at 48, 72, and 96 weeks and survival time 
estimated using Kaplan-Meier methods 
• 
Changes in quality of life over time, as measured by the EORTC QLQ-C30 (a general 
questionnaire for cancer) and the QLQ-NMIBC24 (a specific questionnaire for NMIBC disease) 


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Additionally, patients with appearance of new high-grade disease (ie, new high-grade papillary disease in 
patients with CIS only or new CIS in patients with papillary disease only) will be classified as treatment 
failures in EFS analyses, as will patients with CIS at baseline whose CIS lesions have not resolved by the 
12-week cystoscopy, or who have recurrent CIS at later cystoscopies.  
At each follow-up visit, response of existing lesions and presence of any new lesions will be evaluated (by 
direct visualization and biopsies as needed) and reported in the eCRF. Recurrences must be proven and 
documented by biopsy.  
A biopsy will be performed at screening and when indicated by direct visualization at other visits for 
purposes of staging and grading.  
The laboratory results from pathology specimens (samples taken from re-TUR of tumors) will be reviewed 
by the study investigator. These laboratory results will be provided to the investigator from the certified 
and/or accredited laboratory local to the site, where the samples were processed. If there is no certified 
and/or accredited laboratory on site, the specimen may be shipped to another agreed upon certified 
and/or accredited laboratory for analysis and reporting of results to the study investigator. There is no 
central laboratory review and/or evaluation requirement in this study. For these efficacy analyses, 
recurrence will be considered biopsy proven and/or sufficiently documented following a local investigative 
pathology review that deems the specimen as positive.  
In the case where a patient consistently has positive cystoscopy or cytology results (3 or more) but 
repeated negative biopsy, the patient will not be considered a treatment failure for the EFS analyses. 
5.2 
Safety Endpoints 
The safety endpoint is occurrence of treatment-emergent adverse events (TEAEs) according to Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0, regardless of relationship to study 
medication. 
 
 


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6. 
Analysis Populations 
The following analysis sets will be evaluated and used for presentation of the data: 
Full Analysis Set (FAS) 
The FAS will include all patients who are enrolled in the study (ie, signed the ICF) and received at least 
1 dose of study medication. This population will be used for efficacy and safety analyses. 
Per-Protocol Set 
A per-protocol set will include all patients who met all requirements for the target disease at study entry 
and received all the prescribed treatment without major protocol violations that might have a major effect 
on efficacy analysis. Classes of major protocol deviations will be defined and documented prior to the 
conduct of the primary analysis. These will include but are not limited to significant misuse of the drug 
(eg, wrong dose, missed doses, too long of a delay) and violations of target disease (eg, presence of 
muscle invasion on subsequent review). These analyses will only be performed if more than 10% of 
patients are excluded from the per-protocol set (in either CIS or overall population) respectively based on 
this review. The group of patients excluded will be documented ahead of the protocol snapshot for the 
evaluation of the primary analysis. 


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7. 
Statistical Methodology 
7.1 
Statistical and Analytical Considerations 
7.1.1 Statistical Methods 
Tabulations will be produced for appropriate demographic, baseline, efficacy, and safety parameters. 
Continuous variables will be summarized by reporting the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized using 
frequency tables showing the number and percentage of patients within a particular category, where the 
denominator is the number of non-missing values within category at applicable time point (unless 
otherwise specified). Time-to-event data will be summarized using the Kaplan-Meier method. 
Table 4: Results Reporting Precision 
Statistics 
Degree of Precision 
Min, Max 
The same number of decimal places as recorded in the raw data. 
Mean and Median 
One more decimal place than the raw data. 
SD 
Two more decimal place than the raw data. 
By-patient data listings will be produced for data collected through the study (e.g., CRF and lab). In 
general, the data listings will be sorted by site number concatenated with patient number, visit/collection 
date and visit/collection time (if applicable). All data listings that contain an evaluation date will contain a 
relative study day (Study Day). Pre-treatment and on-treatment study days are numbered relative to the 
day of the first dose of study medication, which is designated as Day 1. The preceding day is Day -1, the 
day before that is Day -2, etc. Baseline will be defined as the last evaluable/non-missing 
observation/assessment prior to the first dose of study product on Cycle 1, Day 1. 
Adverse events will be graded by the Investigator based on the CTCAE, Version 5.0, and will be coded 
for summarization using the Medical Dictionary for Regulatory Activities (MedDRA® Version 21.0 or later). 
Concomitant medications will be coded using the World Health Organization (WHO) Drug Dictionary 
(September 2017 version or later). 
7.1.2 Visit Windows 
All data will be tabulated per the evaluation visit as recorded on the eCRF, even if the assessment is 
outside of the visit window. 
7.1.3 Handling of Missing Data 
Missing data handling rules for AE relationship to treatment and AE severity will be described in Section 
7.4.1. 
For efficacy endpoints, all efforts will be made to avoid missing data. If, however, it does occur, it will be 
handled as follows:  
• 
If a visit has been missed and cytology cystoscopy results are available at the next visit and no 
disease is present, then the earlier visit will be counted as absence of disease.  


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• 
In addition, the count of absence of disease will be based on visit findings, meaning that if a 
patient missed a visit and at the next visit he/she experienced a recurrence, the recurrence will be 
counted only from the day on which evidence was provided. 
Patients with CIS lesions that do not resolve by the 12-week cystoscopy will be classified as EFS events. 
For Kaplan-Meier analyses of EFS, they will be considered to have recurred at 1 day. 
Any patient without tumor in the bladder but presence of tumor in the upper urinary tract will not be 
classified as failures in the CR and EFS analyses and will continue study participation. 
Complete dates will be imputed from partial dates of adverse events and medications solely for the 
purpose of defining treatment emergence for adverse events and prior/concomitant status for 
medications. The imputed dates will not be presented in the listings. Dates will be defined using the 
hierarchy of derivations below. 
Adverse events: 
• 
For onset date: 
o 
If only the day part of the AE onset date is missing and occurs in the same month and year 
as the first dose date of study drug, the date of first dose of study drug will be used as the 
onset date of the AE. Otherwise, the first day of the month will be used to complete the onset 
date of the AE; 
o 
If the day and month parts of the AE onset date are missing and occur in the same year as 
the first dose of study drug, the date of the first dose of study drug will be used as the onset 
date of the AE. Otherwise, January 1st will be used to complete the onset date of the AE; 
o 
If the AE onset date is completely missing, the date of the first dose of study drug will be used 
as the onset date of the AE. 
• 
For end date: 
o 
If only the day part of the AE end date is missing, the last day of the month will be used to 
complete the end date of the AE;  
o 
If the day and month parts of the AE end date are missing, December 31st will be used to 
complete the end date of the AE; 
o 
If the AE end date is completely missing and the onset date of the AE occurs after the date of 
the first dose of study drug, the date of last dose plus 30 days will be used as the AE end 
date. If the AE end date is completely missing and the onset date of the AE occurs prior to 
the date of the first dose of study drug the date of the first dose of study drug will be used as 
the AE end date. 
Medications: 
• 
For onset date: 
o 
If only the day part of the medication onset date is missing and occurs in the same month and 
year as the first dose date of study drug, the date of first dose of study drug will be used as 
the onset date of the medication. Otherwise, the first day of the month will be used to 
complete the onset date of the medication;  


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o 
If the day and month parts of medication onset date are missing and occur in the same year 
as the first dose of study drug, the date of the first dose of study drug will be used as the 
onset date of the medication. Otherwise, January 1st will be used to complete the onset date 
of the medication; 
o 
If the medication onset date is completely missing, the date of the first dose of study drug will 
be used as the onset date of the medication. 
• 
For end date: 
o 
If only the day part of the medication end date is missing, the last day of month will be used 
to complete the end date of the medication;  
o 
If the day and month parts of medication end date are missing, December 31st will be used to 
complete the onset date of the medication; 
o 
If the medication end date is completely missing and the onset date of the medication occurs 
after the date of the first dose of study drug, the date of last dose plus 30 days will be used as 
the medication end date. Otherwise, the date of the first dose of study drug will be used as 
the medication end date.  
The partial dates of medical history and prior treatments (BCG, Bladder cancer, systemic anti-therapy and 
radiotherapy) will not be imputed  as they are already defined as prior to the treatment. No further 
imputation of partial dates to determine the pre/post treatment status is needed. 
7.1.4 Pooling of Investigative Sites 
Data from all participating centers will be pooled prior to analysis. It is anticipated that patient accrual will 
be spread thinly across centers and summaries of data by center would be unlikely to be informative and 
will not, therefore, be provided. However, a summary of treated patients by site will be produced. 
7.1.5 Determination of Sample Size 
Efficacy analyses will generally be conducted for all patients in the FAS, or in the case of the primary 
endpoint of CR rate will be based on all patients in the FAS with CIS at baseline (with or without papillary 
disease. The primary endpoint will be analyzed using a two-sided 95% CI for the CR rate. A total of 140 
treated patients will be included in this study, and it is estimated that between 70 and 100 of these will 
have CIS. Assuming at least 70 patients with CIS, this sample size will provide over 95% power to detect 
a difference in CR rate in CIS patients of 20% and an alternative hypothesis rate of 40% using an exact 
binomial test with a nominal 0.05 two-sided significance level. If 100 CIS patients are treated, the power 
will be approximately 92% to detect a difference from 20% using an alternative hypothesis rate of 35%. 
The power is higher to detect differences from rates lower than 20%. 
7.2 
Patient Characteristics 
7.2.1 Patient Disposition 
The number of patients who complete the planned study treatment (through 96 weeks), are ongoing at 
time of analysis, and do not complete the planned study treatment (through week 96) will be summarized. 
Reasons for patients not completing the study treatment will be categorized as follows: 
• 
Adverse event:  
• 
For patients with CIS at baseline, failure to clear CIS lesions by the 12-week cystoscopy 
• 
Recurrence: high grade NMIBC recurrence requiring discontinuation from the study 


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• 
Death from any cause (with specification of cause of death) 
• 
Withdrawal of consent 
• 
Loss to follow-up 
• 
Sponsor terminated study 
Patient disposition will be presented for all patients. Tabulations will include the following: 
• 
Number of patients signed informed consent 
• 
Number (%) of patients not dosed and reasons not being dosed 
• 
Number (%) of patients dosed 
o 
Number (%) of patients completing the study  
o 
Number (%) of patents ongoing at the time of the database cutoff date 
o 
Number (%) of patients who discontinued the study and reason(s) for discontinuation 
A listing of patient disposition will be generated. A listing of screen failure patients and the 
inclusion/exclusion criteria that were not met (i.e. reason for ineligibility) will be generated. 
7.2.2 Protocol Deviations 
All major protocol deviations will be summarized and listed. 
7.2.3 Demographic and Other Baseline Characteristics 
Demographics and other baseline characteristics will be presented for patients with CIS and overall in 
FAS. The following variables will be listed and summarized using both continuous and categorical 
descriptive statistics: 
• 
Age 
• 
Gender 
• 
Ethnicity 
• 
Race 
• 
ECOG performance status (0, 1, 2) 
• 
Height (cm) 
• 
Weight (kg) 
• 
BMI (kg/m2)  
7.2.4 Treatment Exposure and Compliance 
No dose reduction of BC-819 is planned and no dose adjustments are allowed in the study. 
Study drug exposure will be presented cumulatively. The number of instillations received will be 
summarized using both continuous and categorical descriptive statistics (e.g., mean and frequency). In 


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addition, the total number of induction instillations received, the total number of maintenance instillations 
received, the number of patients with at least 1 missed dose (along with the median number and range of 
the number of missed doses in these patients), and the number of patients with missed dose due to AE 
will be summarized.  
All dosing data will be presented in a data listing. 
7.2.5 Prior Cancer Therapies 
The following prior therapies will be tabulated 
• 
Time from initial NMIBC diagnosis 
• 
Number of prior BCG induction courses (with or without maintenance courses) 
• 
Number of prior NMIBC occurrences (initial diagnosis + recurrences) 
• 
Number of prior BCG instillations (total) 
o 
Number of induction instillations of prior BCG 
o 
Number of maintenance instillations of prior BCG 
• 
Number of prior BCG instillations (most recent course) 
o 
Number of induction instillations of most recent BCG course 
o 
Number of maintenance instillations of most recent BCG course 
• 
Other non-BCG prior bladder cancer therapy overall and by type (ie, MMC or gemcitabine) 
• 
Number with prior systemic anti-cancer therapy 
• 
Tumor staging at study entry 
o 
CIS alone (i.e., not papillary) 
o 
CIS with any papillary 
▪ 
CIS with any HG T1 
▪ 
CIS with HG Ta and no HG T1 
▪ 
CIS with LG Ta or T1 and no HG T1 or HG Ta 
o 
HG Papillary alone (i.e., not CIS) 
▪ 
Any HG T1  
▪ 
HG Ta and no HG T1 
• 
Time from last BCG administration to diagnosis of current recurrence of NMIBC 
All collected information for the diagnosis of history of bladder cancer, prior BCG, other prior bladder 
cancer therapy (non-BCG), prior systemic anti-cancer therapy, prior radiotherapy (related to study 
indication), and prior surgery (related to study indication) will be provided in by-patient data listings. 


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7.2.6 Prior and Concomitant Medications  
Patients may not receive other therapy for bladder cancer, either intravesical or systemic, except for 
anticholinergic treatment and/or chronic use of corticosteroids. Patients may receive therapy for AEs per 
investigator judgment. 
Prior medication is defined as any medication taken prior to the date first dose of study drug. Concomitant 
medication is defined as any medication taken on or after the date of first dose of study drug. Medications 
missing both start and stop dates, or having a start date prior to the first dose of study drug and missing 
the stop date, or having a stop date on or after the last dose of study drug and missing start date will be 
counted as concomitant. 
The partial dates of medications will be imputed using the rule specified in Section 7.1.3. to determine the 
prior and concomitant status.  
Prior and concomitant medications will be coded using the WHO Drug Dictionary, and patient incidence 
will be tabulated by Anatomic Therapeutic Class (ATC) and preferred term (PT). Patients will be counted 
only once for each ATC or preferred name in the event that they have multiple records of the same ATC 
or preferred name in the database. 
All prior and concomitant medications will be included in a by-patient data listing. 
7.2.7 Medical Histories 
Medical history will be coded using MedDRA and will be summarized in frequency tables by System 
Organ Class (SOC) and PT.  
All medical history data will be included in a by-patient data listing.  
7.3 
Efficacy Analysis 
The efficacy endpoints will be analyzed using the FAS. 
7.3.1 Primary Efficacy Analysis 
The primary endpoint of the study is the CR rate in patients with CIS, supported by duration of the CR. 
A CR in patients with CIS is defined as at least one of the following: 
• 
Negative cystoscopy and negative (including atypical) urine cytology 
• 
Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative cytology 
• 
Negative cystoscopy with malignant urine cytology if cancer is found in the upper tract or prostatic 
urethra and random bladder biopsies are negative 
The CR in patients with CIS for this endpoint must be documented on or after the Week 12 response 
assessment. Duration of CR in patients with CIS will be calculated from the documented onset of the CR 
to the assessment where the patient no longer meets the definition of CR. The durability of the CRs will 
be described using Kaplan-Meier plots of the duration of CR in responders. A tabular summary will also 
be created showing the proportion of patients with baseline CIS who are in response at 12, 24, 36, 48, 72 
and 96 weeks using Kaplan-Meier estimates incorporating censoring (note that any patient who achieves 
response within 4 weeks of the planned assessment will be considered to be in response at that 
assessment, ie, a patient who has CR at 16 weeks will be a responder at 12 weeks). A similar tabular 


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summary will be created in the subset of patients with CIS who achieve a CR, that remain in response 12, 
24, 36, 48, 52, 60, 72 and 84 weeks after the onset of response, for this summary, two methods will be 
used one which incorporates censoring and a second where patients who leave the study without losing 
response are considered failures. A by-patient swim lane plot of the time to CR and duration of CR in 
patients with CIS who respond will also be created. A similar summary will be created for the EFS (in all 
patients). 
Sensitivity analyses for duration of response will be performed starting from the time the CIS lesion clears 
to time that new CIS lesions are identified, censoring patients with no CIS but other high-grade disease at 
the time of recurrence and a separate analysis looking at the time from response until any NMIBC is 
found (including low-grade disease). 
A listing of CR rate and duration of response will be provided. 
7.3.2 Secondary Efficacy Analyses 
The date of first dose, disease recurrence, disease progression, progression, death, last tumor 
assessment, last contact, EFS days, and PFS days will be reported in a by-patient listing. 
7.3.2.1 
Event-Free Survival and Time to Recurrence 
EFS is defined as the time from first dose of study medication to the first recurrence of disease or death 
from any cause. Recurrence of disease is defined as  
• 
Appearance of new high-grade disease (ie, new high-grade papillary disease or new CIS) or  
• 
Failure to clear CIS lesions by Week 12 cystoscopy in patients with CIS at baseline 
Recurrence must be biopsy proven. Persistence, appearance, or presence of lower grade disease will not 
be considered recurrence in the primary EFS analyses. Sensitivity analyses will be performed with lower-
grade disease also considered an EFS event. 
Any patient without tumor in the bladder but presence of urothelial carcinoma in the upper urinary tract or 
prostatic urethra will not be classified as failures in these analyses and will continue study participation. 
Additionally, the overall proportion of patients who have high grade recurrence (and subcategories of 
persistent CIS, new CIS, new high-grade papillary disease), development of T2 or greater or metastatic 
disease, cystectomy and death will be summarized for the FAS, and the subgroups with CIS and papillary 
only disease. 
Kaplan-Meier methods will be used to estimate the EFS (ie, percent surviving without a recurrence) and 
the 95% confidence interval at 12, 24, 36, 48, 72, and 96 weeks in all patients in the FAS and the 
subgroup of patients with CIS. The median EFS (ie, median time to recurrence) and its 95% confidence 
interval will also be estimated. Kaplan-Meier plots for EFS will be created. 
A sensitivity analysis will also be performed to analyze EFS using binomial methods where patients are 
considered as being recurrence-free if they have documented recurrence-free survival by the specified 
time point. Only evaluable patients will be included in the analysis. Patients will be considered evaluable if 
they have enough follow-up to determine recurrence status at the time point being summarized or if they 
have discontinued treatment. Exact 95% confidence intervals for EFS will be calculated. 


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A sensitivity analysis for EFS will be performed where if a patient missed a visit and at the next visit 
he/she experienced a recurrence, the recurrence will be counted from the day of the missed assessment. 
An additional sensitivity analysis will be performed where recurrence of any NMIBC, including low-grade 
disease, is counted as an EFS event. 
Time to recurrence is defined as first dose of study medication to the first recurrence of disease. Patients 
without a recurrence event (including death) will have their event time censored at the last recurrence-
free disease assessment. All analyses performed for EFS, including all sensitivity analyses, will be 
performed for time to recurrence. 
7.3.2.2 
Progression-Free Survival and Time to Progression 
PFS is defined as the time from first dose of study medication to the first observation of disease 
progression or death. Progression is defined as the development of T2 or greater disease, which includes 
lymph node disease and distant metastasis.  
Kaplan-Meier methods will be used to estimate the PFS (ie, percent surviving without a PFS event) and 
the 95% confidence interval at 48, 72, and 96 weeks in all patients in the FAS and the subgroup of 
patients with CIS. The median PFS and its 95% confidence interval will also be estimated. Kaplan-Meier 
plots for PFS will be created. 
A sensitivity analysis of PFS will also be performed, which also includes an increase in stage from Ta or 
CIS to T1 as a progression event. 
Time to progression is defined as first dose of study medication to the first observation of disease 
progression. Patients without a progression event (including death) will have their event time censored at 
the last progression-free disease assessment. All analyses performed for PFS, including all sensitivity 
analyses, will be performed for time to progression. 
7.3.2.3 
Overall Survival 
OS is defined as the time first dose of study medication until death. Kaplan-Meier methods will be used to 
estimate the OS (ie, percent surviving without death) and the 95% confidence interval at 48, 72, and 96 
weeks in all patients in the FAS and the subgroup of patients with CIS. The median OS and its 95% 
confidence interval will also be estimated. Kaplan-Meier plots for OS will be created. 
7.3.2.4 
Quality of Life 
Quality of life will be assessed using the EORTC QLQ-C30 (a general questionnaire for cancer) and the 
QLQ-NMIBC24 (a specific questionnaire for NMIBC disease). The questionnaire is administered at 
baseline (Day 1) and Weeks 21 and 45 prior to any clinical measurements, assessments, evaluations, or 
procedures being performed. 
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five 
functional scales (physical, role, emotional, cognitive, and social), three symptom scales (fatigue, nausea 
and vomiting, and pain), a global health status/quality of life scale, and six single items (dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Each of the multi-item scales 
includes a different set of items and no item occurs in more than one scale.  
Each scale will be summarized on a 0-100 scale according to the scoring manual (Fayers). For functional 
scales and the global health status/quality of life scale, a higher score corresponds to greater function or 
quality of life. For symptom scales, a higher score corresponds to greater symptom burden. 


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The QLQ-NMIBC24 is composed of both multi-item scales and single-item measures related to NMIBC. 
These include five multi-item symptom scales (urinary symptoms, malaise, future worries, bloating and 
flatulence, and male sexual problems), one multi-item functional scale (sexual function) and five single-
item measures (intravesical treatment issues, sexual intimacy, risk of contaminating a partner, sexual 
enjoyment, and female sexual problems).  
Each scale in the QLQ-NMIBC24 will be summarized on a 0-100 scale similar to the scoring described for 
the QLQ-C30 (Fayers; Blazeby). For functional scales (sexual function and sexual enjoyment), a higher 
score corresponds to greater function or quality of life. For symptom scales, a higher score corresponds 
to greater symptom burden. 
Each scale from the two questionnaires will be summarized descriptively at baseline and the subsequent 
visits using the actual score at the visit and the change from baseline at the visit. Means, standard 
deviations, medians, range, and the 95% confidence interval for the mean will be summarized.  
7.4 
Safety Analysis 
Safety will be assessed by evaluation of AEs and clinical laboratory results. All safety analyses will be 
performed using FAS. 
7.4.1 Adverse Events 
Adverse events will be graded according to the NCI CTCAE Version 5.0, coded using the MedDRA 
coding system, and displayed in tables and data listings by system organ class (SOC) and preferred term 
(PT). 
A TEAE is any AE occurring after start of study medication or pre-existing medical condition that worsens 
in intensity after start of study medication and within 30 days of the last administration of study medication 
or is deemed to be related to study medication. AEs that occur after 30 days of the last administration of 
study medication and are not related to study medication will not be considered TEAEs. 
All AEs occurring after the patient signs the ICF will be recorded, but only the TEAEs will be summarized 
in tables. AEs occurring between signing of the ICF and start of study medication will be included in 
separate listings from TEAEs. 
If the start date of an AE is partially or completely missing, the date will be imputed using the rules 
specified in Section 7.1.3 to determine the treatment emergence. . The AE will be assumed to be 
treatment-emergent if it cannot be definitively shown that the AE did not occur or worsen during the 
treatment-emergent period (worst case approach). 
Adverse events are summarized by patient incidence rates; therefore, in any tabulation, a patient 
contributes only once to the count for a given SOC or PT (i.e., the most related occurrence or the most 
intense occurrence). Missing relationship will be considered definitely related to BC-819. 
An overall AE incidence summary table will be produced and will include: 
• 
The number and percentage of patients reporting at least 1 TEAE 
• 
The number and percentage of patients reporting at least 1 serious AE (SAE) 
• 
The number and percentage of patients reporting at least 1 TEAE with toxicity grade of 3 or 
higher 
• 
The number and percentage of patients reporting a TEAE leading to withdrawal of study drug 


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• 
The number and percentage of patients reporting a TEAE leading to study drug interruption 
• 
The number and percentage of patients reporting a TEAE leading to death 
• 
The number and percentage of patients reporting at least 1 TEAE related to treatment 
• 
The number and percentage of patients reporting at least 1 treatment-related TEAE with toxicity 
grade of 3 or higher  
• 
The number and percentage of patients reporting at least 1 treatment-related serious AE (SAE) 
• 
The number and percentage of patients reporting a treatment-related TEAE leading to death 
Tabulations by SOC and PT will be produced for all TEAEs, treatment-related TEAEs, SAEs, treatment-
related SAEs, TEAEs Grade ≥3 (including columns for highest grade 3, 4, and 5), treatment-related 
TEAEs Grade ≥3 (including columns for highest grade 3, 4, and 5),TEAEs leading to study drug 
withdrawal, TEAEs leading to study drug interruption, treatment-related TEAEs leading to death and 
TEAEs, treatment-related TEAEs and SAEs by maximum toxicity grade. These will be presented by SOC 
and PT, sorted by decreasing frequency. The tabulations will be also be presented separately by PT, sort 
by decreasing frequency. All tabulations will be presented by overall patients. Additionally, overall 
summary, TEAEs, treatment-related TEAEs,  TEAEs Grade ≥3,  treatment-related TEAEs Grade ≥3, 
SAE, treatment-related SAE, treatment-related death will also be tabulated by patients with baseline CIS. 
In addition to standard MedDRA SOC and PT tables of AEs, a composite class of urinary tract‒related 
AEs will also be created and the incidence and severity of AEs in this composite class tabulated. SOC 
and PTs for urinary tract‒related AEs are shown in Table 4. 
Table 4 
Urinary Tract‒Related Adverse Events 
System Organ Class 
Preferred Term 
Infections and infestations 
Urinary tract infection 
Urosepsis 
Investigations 
Blood creatinine increased 
Renal and urinary disorders 
Any 
No formal hypothesis-testing analysis of AE incidence rates will be performed. All AEs occurring on-study 
will be provided in data listings. By-patient listings also will be provided for the following: SAEs, AEs 
leading to study drug withdrawal, and AEs leading to study drug interruption. 
7.4.2 Physical Examination 
Physical examinations will be performed at the time points specified in 


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Table 1, Table 2, and Table 3. Findings will be listed. 
7.4.3 Vital Signs 
Vital signs will be performed at the time points specified in 


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Table 1, Table 2, and Table 3. The actual value and change from baseline to each visit and at end of 
study will be descriptively summarized by visit/assessment for vital signs (i.e., systolic and diastolic blood 
pressure, pulse rate, respiratory rate, temperature, and body weight). 
Height is measured at screening only. All vital sign data will be reported in a by-patient listing. 
7.4.4 Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed at baseline for patients with a history or symptoms 
of cardiac or respiratory abnormality 12-lead if not performed within 1 month of study entry.  
Electrocardiogram data will be provided in a by-patient listing. 
7.4.5 Laboratory Parameters 
Safety laboratory assessments will be performed at the time points specified in 


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Table 1, Table 2, and Table 3. 
The actual value and change from baseline to each visit and at end of study for each laboratory 
parameter reported in Table 5 will be descriptively summarized. Shift from baseline to highest CTCAE 
grade tables for key parameter will also be presented. The number and percentage of patients with any 
laboratory CTCAE grade increase from baseline and a laboratory CTCAE grade increase from baseline to 
Grade 3-4 will be summarized.  
Laboratory results will be included in by-patient listings. 
Table 5 
Clinical Laboratory Parameters 
Hematology 
Chemistry 
Urinalysis 
Hemoglobin 
Albumin 
Blood  
Total red blood cell count 
Alkaline phosphatase 
Leukocytes 
Total white blood cell (WBC) count 
Aspartate aminotransferase 
Glucose 
absolute values for individual WBC 
types 
Alanine aminotransferase 
Ketones 
Platelets 
Bicarbonate 
Nitrites 
 
Bilirubin 
pH 
 
Blood urea nitrogen 
Protein 
 
Calcium  
Specific gravity 
 
Chloride 
Microscopic:  
WBC, red blood cells, 
bacteria, epithelial 
cells, crystals (with 
type identified), and 
mucus 
 
Creatinine 
 
Glucose 
 
Potassium 
 
Sodium 
 
Total protein 
7.4.6 Evaluation of Performance Status 
The frequency distribution of Eastern Cooperative Oncology Group (ECOG) performance status will be 
collected at screening and at each study visit in conjunction with the physical examination. ECOG 
performance assessments will be summarized and listed. 
Table 6 
Eastern Cooperative Oncology Group Performance Status: Scored 0 (Normal 
Function) through 5 (Dead) 
ECOG PERFORMANCE STATUSa 
Grade 
ECOG 
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, eg, light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
 


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7.5 
Interim Analysis 
The first 35 patients in the study are to be CIS patients (with or without papillary disease). An interim 
analysis for futility will be conducted using the response data in these patients. If 9 or fewer of these first 
35 patients achieve CR, the study may be stopped for futility. If 10 or more patients achieve a CR, then 
the study will continue and all patients meeting entry criteria may be enrolled (including those with 
papillary disease without CIS). The enrollment will be paused after 35 patients to evaluate this data 
unless 10 or more responses have already been documented when the 35th CIS patient is enrolled. 
When the true CR rate is 40% or higher, the probability of proceeding with 10 or more CRs out of the first 
35 patients is over 94%. When the true CR rate is 15% or lower, the probability of 9 or fewer responses is 
over 97%. 
The interim analysis will include summaries of patient disposition, demographics, baseline characteristics, 
study drug exposure, efficacy and safety data. The summary of efficacy data will include the analysis of 
the primary endpoint described in Section 7.3.1. This includes a summary of the CR rate, duration of 
response, and a swim-lane plot. The summary of safety data will include the analyses specified in Section 
7.4.1 for TEAEs, treatment-related TEAEs, SAEs, treatment-related SAEs, TEAEs Grade ≥3, and 
treatment-related TEAEs Grade ≥3 by SOC and PT and by PT alone. 
The TLF shells of the interim analysis will be provided in the appendix. 
7.6 
Subgroup Analysis 
For efficacy, subgroup analyses will be performed for the CR rate, duration of response, and EFS rate at 
48 weeks. The EFS rate at 48 weeks will be based on Kaplan-Meier methods. Subgroup analyses will be 
performed for the following pre-planned subgroups: 
• 
Tumor staging (CIS alone, CIS with any papillary, HG papillary without CIS [EFS only]) 
• 
ECOG 0-1 vs 2 
• 
Recurrence ≤ 6 months from last BCG vs > 6 months 
• 
Age (≥65 vs <65) 
• 
Gender 
• 
Race (only if there are more than 10 patients of non-White race) 
• 
BCG unresponsive at most recent recurrence vs. not 
Subgroup analyses for the CR rate will be conducted in patients with CIS at baseline, while subgroup 
analyses for duration of response will be conducted in patients with CIS at baseline with a CR. Subgroup 
analyses for EFS will be performed for patients in the FAS. 
For the key safety analysis (TEAE, treatment-related TEAE, SAE, treatment-related SAE, TEAEs Grade 
≥3, and treatment-related TEAEs Grade ≥3) the analysis will be performed by below planned subgroups: 
• 
Age (≥65 vs <65) 
• 
Gender 


Statistical Analysis Plan for Phase I/II Oncology Studies 
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This document is confidential. 
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• 
Race 
7.7 
Changes to Methods Planned in the Protocol  
There are no changes from the analysis planned in the protocol. 


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8. 
Tables, Listings, And Figures 
8.1 
Programming Guidelines 
Computer-generated output will adhere to the following specifications. The standard operating procedures 
(SOPs) of Syneos Health Clinical will be followed in the creation and quality control of all tables, listings 
and figures. 
8.1.1 Format of Output 
Unless otherwise specified, all computer-generated output should be produced in landscape mode. 
Required margins: at least 1.25 inches on top (the binding margin [or left for portrait output]), at least 1 
inch on right, left, and bottom. All output should have the Sponsor name, protocol number, the type of 
delivery, and page number. Tables/listings/figures should be internally paginated in relation to total length 
(i.e., page number should appear sequentially as page n of N, where N is the total number of pages in the 
table). All output should have the following header at the top of the page:  
Sponsor Name 
Protocol XXXXXXX 
Confidential 
Page n of N 
 
1. Output numeration will conform to International Conference on Harmonization (ICH) 
recommendations. The study population should be identified immediately following the title. 
2. Column headings should be in initial upper-case characters. 
3. For numeric variables, include “unit” in column or row headings where appropriate. 
4. Footnotes should be single spaced, but separated by at least a double space from the bottom line 
of the table. The notes are aligned vertically by the left vertical border of the table. 
5. If the categories are not ordered (e.g., race), then only those categories for which there is at least 
1 patient represented in 1 or more groups should be included. 
6. An Unknown or Missing category should be added to any parameter for which information is not 
available for 1 or more patients. 
7. Listings should be sorted by dose levels and patient numbers. 
8. In a listing, display the patient number only once for the patient with multiple records. If a patient’s 
records run into multiple pages, display the patient number once for every page. 
8.1.2 Format of Data 
1. Unless otherwise specified for continuous variables, the estimated mean, SD and median for a 
set of values should be printed out to 1 more significant digit than the individual units of 
measurement. The minimum and maximum should report the same significant digits as the 
original values. 
2. Data in columns of a table should be formatted as follows: 
• 
Alphanumeric values are left-justified.  
• 
Whole numbers (e.g., counts) are right-justified. 


Statistical Analysis Plan for Phase I/II Oncology Studies 
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• 
Numbers containing fractional portions are decimal aligned. 
3. Unless otherwise specified, percentage values should be printed with 1 digit to the right of the 
decimal point (e.g., 12.8%, 5.4%). Less-than signs “0.1%” should be printed when values are 
0.0 and 0.1% (not 0.0%). 
4. Missing data should be represented on patient listings as either a hyphen (“-“) with a 
corresponding footnote (“ - = unknown or not evaluated”), or as “N/A,” with the footnote “N/A = not 
applicable,” whichever is appropriate. 
5. Dates should be printed in SAS ISO 8601 format (“YYYY-MM-DD”: 2000-JUL-01). Missing 
portions of dates should be represented on patient listings as missing (2000-JUL). Dates that are 
missing because they are not applicable for the patient are output as “N/A”, unless otherwise 
specified. 
6. Time should be printed in SAS TIME5.format (“HH:MM”: 17:30). Missing portions of time should 
be represented on patient listings as dashes (--:30). Times that are missing because they are not 
applicable for the patient are output as “N/A”, unless otherwise specified. 
8.2 
Table of Contents for Tables, Listings and Figures 
8.2.1 List of Tables 
To be provided with TLF Shells 
8.2.2 List of Listings 
To be provided with TLF Shells 
8.2.3 List of Figures 
To be provided with TLF Shells 
 
 


Statistical Analysis Plan for Phase I/II Oncology Studies 
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9. 
References 
American Cancer Society. Cancer facts & figures 2016. Atlanta: American Cancer Society; 
2016.http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-
047079.pdf . Accessed 09 February 2018. 
Blazeby JM, Hall E, Aaronson NK, et al. Validation and reliability testing of the EORTC QLQ-NMIBC24 
questionnaire module to assess patient-reported outcomes in non-muscle-invasive bladder 
cancer. Eur Urol. 2014;66(6):1148–1156. doi:10.1016/j.eururo.2014.02.034 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the EORTC 
Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Brussels 2001. 
Fernandez-Gomez J, Madero R, Solsona E, Unda M, Martinez-Piñeiro L, Gonzalez M, et al. Predicting 
nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus 
Calmette-Guerin: the CUETO scoring model. J Urol. 2009;182(5):2195-2203. 
Food and Drug Administration. Guidance for Industry: BCG-unresponsive nonmuscle invasive bladder 
cancer: developing drugs and biologics for 
treatment.https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/UCM529600.pdf. February 2018. Accessed 23 February 2018. 
Lamm DL. Superficial bladder cancer. Curr Treat Options Oncol. 2002;3(5):403-411. 
Madeb R, Golijanin D, Noyes K, Fisher S, Stephenson JJ, Long SR, et al. Treatment of nonmuscle 
invading bladder cancer: do physicians in the United States practice evidence based medicine? 
The use and economic implications of intravesical chemotherapy after transurethral resection of 
bladder tumors. Cancer. 2009;115(12):2660-2670. 
Morgan TM, Keegan KA, Clark PE. Bladder cancer. Curr Opin Oncol. 2011;23(3):275-282. 
Shelley MD, Mason MD, Kynaston H. Intravesical therapy for superficial bladder cancer: a systematic 
review of randomised trials and meta-analyses. Cancer Treat Rev. 2010;36(3):195-205. 
Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of 
progression in patients with superficial bladder cancer: a meta-analysis of the published results of 
randomized clinical trials. J Urol. 2002;168(5):1964-1970. 
Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting 
recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC 
risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 
2006;49(3):466-465; discussion 475-477. 
van Rhijn BW, Burger M, Lotan Y, Solsona E, Stief CG, Sylvester RJ, et al. Recurrence and progression 
of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur 
Urol. 2009;56(3):430-442. 


Statistical Analysis Plan for Phase I/II Oncology Studies 
Sponsor: Anchiano Therapeutics Israel Ltd., Protocol No.: BC-819-18-204 
 
 
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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10. Appendices 
10.1 
Table of Contents of Interim Analysis 
Table 14.1.1.2 Summary of Patient Disposition  
Full Analysis Set 
Table 14.1.2 Summary of Demographic and Baseline Characteristics   
Full Analysis Set 
Table 14.1.3 Summary of Major Protocol Deviations  
Full Analysis Set 
Table 14.1.4 Summary of Prior Cancer Therapy  
Full Analysis Set 
Table 14.1.6 Summary of Concomitant Medication  
Full Analysis Set 
Table 14.1.7 Summary of Study Drug Exposure  
Full Analysis Set 
Table 14.2.1.1.1 Summary of Complete Response Rate Patients with CIS at 
Baseline 
Full Analysis Set 
Table 14.2.1.1.2 Summary of Detailed Response for Each Patient at Week 12. 
Full Analysis Set 
Table 14.2.1.2.1 Summary of Duration of Complete Response Patients with CIS at 
Baseline with Complete Response 
Full Analysis Set 
Table 14.2.1.2.2 Kaplan-Meier Estimate of Duration of Complete Response 
Patients with CIS at Baseline with Complete Response 
Full Analysis Set 
Table 14.2.2.1.1 Kaplan-Meier Estimate of Event-Free Survival 
Full Analysis Set 
Table 14.2.2.1.2 Sensitivity Analysis of Summary of Event-Free Survival – Binomial 
Method 
Full Analysis Set 
Table 14.2.2.2.1 Kaplan-Meier Estimate of Time to Recurrence 
Full Analysis Set 
Table 14.2.2.2.2 Sensitivity Analysis of Summary of Time to Recurrence – Binomial 
Method 
Full Analysis Set 
Table 14.3.1.1.2 Overall Summary of Treatment-Emergent Adverse Events - 
Patients with Baseline CIS 
Full Analysis Set 
Table 14.3.1.2.4 Summary of Treatment-Emergent Adverse Events by Preferred 
Term - Patients with Baseline CIS 
Full Analysis Set 
Table 14.3.1.5.4 Summary of Treatment Related Treatment-Emergent Adverse 
Events by Preferred Term - Patients with Baseline CIS 
Full Analysis Set 
Table 14.3.1.8.4 Summary of Serious Adverse Events by Preferred Term - Patients 
with Baseline CIS 
Full Analysis Set 
Table 14.3.1.9.4 Summary of Treatment Related Serious Adverse Events by 
Preferred Term - Patients with Baseline CIS 
Full Analysis Set 
Table 14.3.1.3.4 Summary of Treatment-Emergent Adverse Events by Preferred 
Term and Maximum Severity - Patients with Baseline CIS 
Full Analysis Set 
Table 14.3.1.12.4 Summary of Treatment Related Treatment-Emergent Adverse 
Events by Preferred Term and Grade - Patients with Baseline CIS 
Full Analysis Set 
Figure 14.2.1.2.1 Kaplan-Meier Plot for Duration of Response for Patients with CIS 
at Baseline with Complete Response 
Full Analysis Set 
Figure 14.2.1.2.2 Swim Lane Plot for Time to Complete Response and Duration of 
Response for Patients with CIS at Baseline with Complete Response 
Full Analysis Set 
Figure 14.2.2.1 Kaplan-Meier Plot for Event-Free Survival 
Full Analysis Set 
Figure 14.2.2.2 Kaplan-Meier Plot for Time to Recurrence 
Full Analysis Set