Phase 1/2, Placebo-Controlled, Randomized Study to Evaluate the Safety, Immune Response & Clinical Activity of HS-410 in Patients With Non-Muscle Invasive Bladder Cancer Who Have Undergone Transurethral Resection of Bladder Tumor (TURBT)
Phase: PHASE1
Conditions: Bladder Cancer
Sponsor: Heat Biologics

 
 
 
 
 
A Phase 1/2, Placebo-Controlled, Randomized Study to Evaluate the Safety, 
Immune Response and Clinical Activity of HS-410 in Patients with Non-Muscle 
Invasive Bladder Cancer Who Have Undergone Transurethral Resection of 
Bladder Tumor (TURBT)  
 
Protocol HS410-101 
 
 
Amendment History: 
Date 
Version 
Amendment Number 
Amendment Type 
25 Sep 2013 
1.0 
Initial Protocol 
Not applicable 
5 Nov 2013 
2.0 
1 
Non-substantial 
18 Feb 2014 
3.0 
2 
Substantial 
26 June 2014 
4.0 
3 
Substantial 
28 Oct 2014 
5.0 
4 
Non-substantial 
23 Feb 2015 
6.0 
5 
Substantial 
22 Apr 2015 
7.0 
6 
Substantial 
03 Feb 2016 
8.0 
7 
Substantial 
 
CONFIDENTIAL 
Information in this protocol is confidential and should not be disclosed, other than to those directly involved 
in the execution of the ethical review of the study, without written authorization from the sponsor.  It is 
however, permissible to provide information to a participant to obtain informed consent. 
 
 

Heat Biologics, Inc. 
 
Investigational Product: Vesigenurtacel-L 
Protocol HS410-101 
 
CONFIDENTIAL 
 
 
Version 8.0; 03 Feb 2016 
 
Page 2 of 86 
 
 
Sponsor: 
Melissa Price, PhD 
 
Heat Biologics, Inc. 
 
 
 
 
 
801 Capitola Drive, Suite 12 
 
 
 
 
 
Durham, NC  27713 
 
 
 
 
 
Tel:  919-240-7133 
 
 
 
 
 
 
 
Medical Monitor: 
 
 
Pia Lynch, M.D. 
 
 
 
 
 
Drug Safety Solutions 
 
 
 
 
 
5205 Indigo Moon Way  
 
 
 
 
 
Raleigh, NC  27613 
 
 
 
 
 
Tel:  770-826-1096 
 
 
 
 
 
Fax: 678-828-5549 
 
 
Primary Investigator: 
 
 
Gary D. Steinberg, M.D. 
The Bruce and Beth White Family Professor and Director of 
Urologic Oncology 
Vice Chairman Section of Urology 
University of Chicago Medical Center 
5841 S. Maryland Avenue, MC 6038 
Chicago, Illinois  60637 
Tel: 773-702-3080 
Fax: 773-702-1001 
 
 
 
 
 
 
 
 
 
 
 

Heat Biologics, Inc. 
 
Investigational Product: Vesigenurtacel-L 
Protocol HS410-101 
 
CONFIDENTIAL 
 
 
Version 8.0; 03 Feb 2016 
 
Page 4 of 86 
 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
Protocol Number: 
HS410-101 
 
Protocol Title: 
 A Phase 1/2, Placebo-Controlled, Randomized Study to Evaluate the Safety, Immune 
Response and Clinical Activity of HS-410 in Patients with Non-Muscle Invasive 
Bladder Cancer Who Have Undergone Transurethral Resection of Bladder Tumor 
(TURBT)  
Version/Date: 
Version 8.0 (03 Feb 2016) 
 
I understand that all documentation provided to me by Heat Biologics, Inc., or its designated 
representative(s) concerning this study that has not been published previously will be kept in the strictest 
confidence.  This documentation includes the study protocol, investigator’s brochure, case report forms, 
and other scientific data. 
This study will not commence without the prior written approval of a properly constituted Institutional 
Review Board (IRB) and Institutional BioSafety Committee (IBC), as applicable.  No changes will be made 
to the study protocol without the prior written approval of Heat Biologics, Inc., and the IRB and/or IBC, 
except where necessary to eliminate an immediate hazard to the patient. 
I have read and understand the clinical protocol and agree to conduct the clinical study in compliance with 
the protocol, Good Clinical Practice, the Declaration of Helsinki (2008), United States and other applicable 
local regulatory requirements.  
 
Principal Investigator Name, printed: ____________________________________________ 
 
Principal Investigator Signature:_________________________________________________ 
 
Date: ________________________ 
 
 

Heat Biologics, Inc. 
 
Investigational Product: Vesigenurtacel-L 
Protocol HS410-101 
 
CONFIDENTIAL 
 
 
Version 8.0; 03 Feb 2016 
 
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CLINICAL PROTOCOL SYNOPSIS 
Trial title: 
A Phase 1/2, Placebo-Controlled, Randomized Study to Evaluate the Safety, Immune 
Response and Clinical Activity of HS-410 in Patients with Non-Muscle Invasive Bladder 
Cancer Who Have Undergone Transurethral Resection of Bladder Tumor (TURBT)  
Study objectives: 
Primary Objective:  
 
Phase 1: To characterize the safety and tolerability of low dose monotherapy 
vaccination with vesigenurtacel-L in patients with non-muscle invasive bladder 
cancer. 
 
Phase 2:  
o 
Arms 1, 2, and 3: To evaluate 1-year disease-free survival in patients with 
non-muscle invasive bladder cancer treated with BCG in combination with 
blinded study product (one of two doses of vesigenurtacel-L or placebo). 
o 
Arm 4: To evaluate 1-year disease-free survival in patients with non-muscle 
invasive bladder cancer treated with high dose vesigenurtacel-L monotherapy. 
Secondary Objectives:  
 
To evaluate the safety of the combination of vesigenurtacel-L and BCG (Phase 2 
only) 
 
To evaluate the safety of high dose vesigenurtacel-L monotherapy (Phase 2 only) 
 
To evaluate the proportion of patients with recurrence at 3, 6, 12, 18, and 24 months 
 
To evaluate the proportion of patients with progressive disease at 3, 6, 12, 18, and 
24 months 
 
To evaluate disease-free survival at 3, 6, 18 and 24 months 
 
To evaluate overall disease-free survival 
 
To evaluate overall survival (OS) 
 
To evaluate the proportion of patients undergoing post-treatment TURBT or 
fulguration by 12 and 24 months 
 
To evaluate the proportion of patients undergoing cystectomy by 12 and 24 months  
 
To evaluate the proportion of patients with immunologic response of PBMCs via 
intracellular cytokine staining (ICS) by flow cytometry and/or ELISPOT on CD8+ 
cells following vesigenurtacel-L vaccination  
Exploratory Objectives: 
 
Immunologic response of PBMCs (analysis of surface markers, CD3, CD4, CD8, 
CD19, CD25, CD45, CD56, FoxP3, and degranulation) and stimulation analysis 
via ICS of IFNγ and granzyme B (gzB).  
 
Total PBMC counts by flow cytometry, including lymphocyte subsets (B cells, 
helper T-cells, cytotoxic T-cells, NK cells and T-reg)  
 
Evaluation of tumor tissue obtained prior to treatment for antigen expression, 
expression of major histocompatibility complex (MHC) class I, and expression of 
immunosuppressive molecules 
 
Evaluation of tumor tissue obtained from repeat biopsy, if clinically indicated, for 
presence of tumor infiltrating T-lymphocytes (TILs) 
 
T cell receptor sequencing of PBMCs and tumor tissue to determine correlation 
between clonally expanded T cell populations and other endpoints 
 
Immune cell infiltration and inflammatory cytokine levels in urine (Phase 2 only) 
Trial centers: 
Up to 20 centers 

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Investigational Product: Vesigenurtacel-L 
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CONFIDENTIAL 
 
 
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Sample size: 
Approximately 110 patients will be enrolled in the study in order to obtain 10 patients in 
Phase 1 and 100 patients in Phase 2. 
Trial design: 
 
Patients with non-muscle invasive bladder cancer who have either undergone TURBT or 
fulguration for the removal of papillary disease or who have carcinoma in situ (CIS) only, 
are candidates for BCG treatment, and are judged to be at an increased risk for recurrence 
are eligible if they are BCG naive or have completed previous BCG treatment >12 months 
prior to the baseline staging procedure.  Phase 2 also allows patients who will not otherwise 
receive BCG. 
 
The Phase 1 portion is an open-label, safety study consisting of one cohort with 10 patients.  
Patients will have previously received 3-6 instillations of weekly intravesical BCG induction 
therapy (as standard of care) followed by low dose intradermal (1 x 106 cells) 
vesigenurtacel-L (HS-410) monotherapy. 
 
In Phase 2, patients will be assigned to treatment groups based on whether they will receive 
induction BCG in the typical post-TURBT window.  If the investigator plans to administer 
BCG, patients will be randomized to one of three blinded (physician-patient), placebo-
controlled groups and receive either intradermal placebo or low dose or high dose (1 x 107 
cells) vesigenurtacel-L in combination with induction and maintenance intravesical BCG.  
If patients will not receive BCG, they will be enrolled into an open-label, non-randomized 
group and receive high dose intradermal vesigenurtacel-L monotherapy. 
 
Phase 1: Patients enrolled in the first cohort within 8-10 weeks of TURBT or fulguration for 
patients with papillary disease and staging procedure for patients with CIS only, and after 
induction BCG will be treated with vesigenurtacel-L weekly for 6 weeks.  After a one-week 
vaccine holiday for disease assessment, patients will receive vesigenurtacel-L for an 
additional 6 weeks followed by three once monthly treatments for a total of 15 vaccinations.  
Patients will be observed weekly to assess the safety of vesigenurtacel-L.  Dosing of the first 
three patients will be staggered by two-week intervals to allow for safety evaluation before 
treating additional patients.  If vesigenurtacel-L appears safe and well-tolerated in the 3 lead-
in patients, dosing will be continued to 10 patients.   
 
Phase 2: Dosing in Phase 2 will begin when all 10 patients have been dosed in the Phase 1 
cohort, at least 6 patients in that cohort have completed the Week 7 safety assessments, and 
the Data Monitoring Committee (DMC) has met to review this data and agreed it is safe to 
advance to Phase 2.  A total of 100 patients will be assigned to four groups: 75 who will 
receive BCG will be randomized to arms combining either low dose vesigenurtacel-L, high 
dose vesigenurtacel-L, or placebo, respectively, with induction and maintenance BCG; 25 
who will not receive BCG will be enrolled in the high dose vesigenurtacel-L monotherapy 
arm. 
 
In the randomized arms, treatment will commence within 6 weeks of the most-recent 
TURBT or fulguration for patients with papillary disease and staging procedure for patients 
with CIS only.  Patients will be treated during an induction phase with weekly intravesical 
BCG and intradermal blinded study product (vesigenurtacel-L or placebo) for 6 weeks 
followed by 6 weekly injections of blinded study product alone.  During a subsequent 
maintenance phase, patients will receive an additional three courses of three once-weekly 
blinded study product injections in combination with intravesical BCG approximately 3, 6, 
and 12 months after initiating induction BCG.  Patients may receive additional courses of 
maintenance BCG in long-term follow-up at the investigator’s discretion but should not 
receive any other cancer therapy prior to disease recurrence/progression. 

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Protocol HS410-101 
 
CONFIDENTIAL 
 
 
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Trial design (con’t): 
In the monotherapy arm, treatment will commence within 6 weeks of the most-recent 
TURBT or fulguration for patients with papillary disease and staging procedure for patients 
with CIS only.  Patients will be treated during an induction phase with weekly intradermal 
vesigenurtacel-L for 12 weeks.  During a subsequent maintenance phase, patients will 
receive an additional three courses of three once-weekly vesigenurtacel-L injections 
approximately 3, 6, and 12 months after initiating induction vesigenurtacel-L. 
 
All patients in both the Phase 1 and Phase 2 portions of the study will have a cystoscopy and 
cytology and, if clinically indicated, a biopsy performed approximately every 3 months for 
2 years then every 6 months for up to a year, study termination, disease progression, or 
recurrence requiring treatment discontinuation, whichever occurs first.  Patients with 
evidence of disease at an assessment may continue on treatment if judged by the investigator 
to be in the patient’s best interest (e.g. would normally receive another course of BCG 
therapy as standard of care (SOC)).  Upon discontinuation of study treatment, additional 
treatment will be at the discretion of the treating physician per SOC.  While treatment may 
continue in the presence of evidence of disease, statistical analysis of disease-free status will 
still follow strict definitions as defined in section 10.1. Evaluation of Disease. 
Dosing regimen: 
Phase 1:  Patients will receive weekly intradermal injections of low dose vesigenurtacel-L 
(1 x 106 cells per dose) for 12 weeks with a vaccine holiday on Week 7 to allow for 
assessment of evidence of disease, followed by three once-monthly injections for a total of 
15 doses. 
 
Phase 2: 
In the randomized arms, patients will receive weekly intradermal injections of blinded study 
drug product (one of two doses of vesigenurtacel-L or placebo) in combination with 
intravesical induction BCG for 6 weeks followed by 6 weeks of blinded study product 
monotherapy with a vaccine holiday on Week 13 to allow for assessment of evidence of 
disease, followed by three courses of three once-weekly injections of blinded study product 
in combination with maintenance BCG for a total of 21 doses. 
 
Vesigenurtacel-L: 
Arm 1: Vesigenurtacel-L consisting of 1 x 106 cells per dose 
Arm 2: Vesigenurtacel-L consisting of 1 x 107 cells per dose 
Arm 3: Placebo 
 
BCG: A full dose according to the investigator’s standard practice should be 
administered.   
 
In the monotherapy arm (Arm 4), patients will receive weekly intradermal injections of high 
dose (1 x 107 cells per dose) vesigenurtacel-L for 12 weeks, followed by three courses of 
three once-weekly vesigenurtacel-L injections for a total of 21 doses. 

Heat Biologics, Inc. 
 
Investigational Product: Vesigenurtacel-L 
Protocol HS410-101 
 
CONFIDENTIAL 
 
 
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Page 8 of 86 
Dosage 
form 
and 
route 
Each study product dose will be divided into the number of injections required to reach the 
number of cells per dose with no more than 0.1 mL per injection (approximately 4-6 
injections), and administered as spatially divided intradermal injections in the same 
extremity to increase volume distribution and enhance antigen presentation to lymph node 
regions shared with the urinary bladder.  Dosing will rotate injection site extremities every 
four timepoints: antero-lateral left thigh, antero-lateral right thigh, left buttock, and right 
buttock.  If injection site reactions are reported as an AE, an alternative injection site may 
be used upon discussion with the sponsor. 
 
Vesigenurtacel-L: Derived from irradiated urothelial bladder cancer cells expressing HLA-
A1 on at least 70% of the cells, producing ≥ 60 ng of gp96-Ig/24h per 1 x 106 cells with ≥ 
70% viability by trypan blue exclusion.  Vesigenurtacel-L is provided as single-dose vials 
either 1) as concentrated frozen liquid, which will require dilution by the pharmacy with 
sterile saline, or 2) as fully-diluted frozen liquid not requiring additional dilution.  In either 
case the final drug product will consist of cells resuspended in buffered saline containing 
human serum albumin (HSA), dimethyl sulfoxide (DMSO), and pentastarch and will be 
delivered at doses of either 1 x 106 cells or 1 x 107 cells. 
 
Placebo: 0.15% Intralipid solution in freezing solution (buffered saline, HSA, DMSO and 
pentastarch) without vesigenurtacel-L cells. 
 
BCG: Intravesical administration according to the institution’s practice 

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Investigational Product: Vesigenurtacel-L 
Protocol HS410-101 
 
CONFIDENTIAL 
 
 
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Eligibility criteria: 
Inclusion Criteria: 
1. Willing and able to sign informed consent and comply with the protocol, including 
clinic visits to receive weekly vesigenurtacel-L injections for 12 doses followed by 
either monthly vesigenurtacel-L injections for three months in Phase 1 or three courses 
of three once-weekly injections in Phase 2. 
2. Histologically or cytologically confirmed non-muscle invasive bladder cancer [Ta, T1 
or Tis (CIS)].  Papillary disease must have been removed by transurethral resection or 
fulguration. 
3. Either  
i. 
High-risk disease, defined as T1 and/or high-grade and/or CIS, or 
ii. 
Intermediate-risk disease defined as Ta low-grade with at least three of the 
following four risk factors: multiple tumors, tumor size > 3cm, early recurrence 
(<1 year from previous staging procedure), or recurrence with a frequency of more 
than once in any 12 month period 
4. Patients must be BCG naïve or have completed previous BCG treatment >12 months 
prior to the baseline staging procedure. 
5. For Phase 2 only: Arms 1, 2, and 3: Suitable, in the opinion of the investigator, to receive 
a 6-week course of induction intravesical BCG in the adjuvant setting within 6 weeks 
following the baseline staging procedure for the current occurrence of non-muscle 
invasive bladder cancer.  Arm 4: Suitable for monotherapy vaccine administration post-
TURBT.  For Phase 1 only: Has previously received 3-6 weekly doses of BCG. 
6. Age ≥18 years 
7. Lab parameters:  
o Albumin ≥2.5 mg/dL  
o Total bilirubin <1.5 mg/dL  
o Alanine transaminase (ALT) and aspartate transaminase (AST) ≤2.5 × upper limit 
of normal (ULN) 
o Serum creatinine ≤2.2mg/dL or calculated creatinine clearance >35 mL/minute per 
the Cockcroft-Gault formula 
o White blood cell (WBC) count ≥4,000/mm3 with an absolute neutrophil count 
≥1,500/mm3 
o Hemoglobin ≥9 g/dL 
o Platelet count ≥75,000/mm3 
8. Women of childbearing potential or men of fathering potential must use adequate birth 
control measures (e.g., abstinence, oral contraceptives, intrauterine device, barrier 
method with spermicide, or surgical sterilization) during the study and for 6 months 
after receiving the last administration of study medication. Female patients of 
childbearing potential must test negative for pregnancy prior to enrolling in the trial. 

Heat Biologics, Inc. 
 
Investigational Product: Vesigenurtacel-L 
Protocol HS410-101 
 
CONFIDENTIAL 
 
 
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Eligibility 
criteria 
(con’t): 
Exclusion Criteria: 
1. Known human immunodeficiency virus (HIV) infection or immunodeficiency 
disorders, either primary or acquired 
2. Infections or concurrent illness, requiring active therapy 
3. Any condition requiring active steroid or other immunosuppressive therapy 
4. Active malignancies within 12 months with the exception of those with a negligible 
risk of metastasis or death treated with expected curative outcome 
5. Prior prostatic pelvic radiation within the past 12 months 
6. Known history of clinically significant cardiac impairment, congestive heart failure 
> New York Heart Association (NYHA) cardiac disease classification Class II, 
unstable angina, or myocardial infarction during the previous three months 
7. Known current alcohol or chemical abuse, or mental or psychiatric condition 
precluding compliance with the protocol 
8. Pregnant or nursing 
9. Known allergy to soy, egg, or peanut products 
10. Receiving another investigational agent (30 day wash-out required prior to first 
dose) 
11. Neo-adjuvant therapy prior to the baseline staging procedure for the current 
occurrence of non-muscle invasive bladder cancer 
12. Prior treatment with a cancer vaccine for this indication 
13. Prior vaccination with BCG for tuberculosis disease 
14. Prior splenectomy 
Safety monitoring: 
All patients will be assessed for pre-existing symptoms during screening (from the date of 
signature of informed consent to immediately prior to first dose of study product). Symptoms 
will be documented as AEs only if related to study procedures from the first dose of study 
product until four weeks after the last dose of study product or until death, whichever occurs 
first.  All AEs will be followed until the event has subsided or, in the case of permanent 
impairment, until the condition stabilizes.  All patients who receive at least one dose of study 
product will be included in the safety analysis. 
 
The Primary Investigator and the Medical Monitor will assess the safety of vesigenurtacel-L 
on an ongoing basis during trial enrollment and dosing.  A Data Monitoring Committee 
(DMC) will provide dose expansion recommendations during Phase 1 and will continue 
safety surveillance in Phase 2. 
 
In order to continually monitor safety during the Phase 2 portion, the DMC will review 
(unblinded) all available safety data after at least one patient has been randomized to each 
of the active arms and has completed four weeks of treatment and then after 3, 6, and 12 
patients in each randomized treatment group have completed the Week 7 assessment.  
Subsequently the DMC will review all available safety data at regular three-monthly 
intervals until study completion or should they determine that review is no longer necessary.  
Additionally, the DMC will convene on an ad-hoc basis should any patient experience a 
Grade 3 or higher adverse event (considered by the investigator to be related to 
vesigenurtacel-L) at any time during the study.  Depending on emerging data, the DMC will 
have the authority to suspend allocation to a particular study treatment and require that 
additional patients are studied in a particular arm or at a particular dose level of 
vesigenurtacel-L, in order to further characterize the safety profile. 

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Investigational Product: Vesigenurtacel-L 
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Efficacy parameters: 
Primary Endpoints:  
Phase 1: Safety and tolerability 
Phase 2: 1-year Disease-Free Survival (1-yr DFS) 
 
Secondary Endpoints: 
 
Safety of the combination of vesigenurtacel-L and BCG (Phase 2 only)  
 
Safety of high dose vesigenurtacel-L monotherapy (Phase 2 only) 
 
Proportion of patients with recurrence at 3, 6, 12, 18, and 24 months 
 
Proportion of patients with progressive disease at 3, 6, 12, 18, and 24 months 
 
Disease-free survival (DFS) at 3, 6, 18, and 24 months  
 
Overall DFS 
 
Overall Survival (OS)  
 
Proportion of patients undergoing post-treatment TURBT or fulguration by 12 and 
24 months 
 
Proportion of patients undergoing cystectomy by 12 and 24 months  
 
Proportion of patients with immunologic response of PBMCs via intracellular 
cytokine staining (ICS) by flow cytometry and/or ELISPOT on CD8+ cells after 
receiving vesigenurtacel-L treatment as compared to baseline 
 
Exploratory Endpoints: 
 
Immunologic response of PBMCs (analysis of surface markers, CD3, CD4, CD8, 
CD19, CD25, CD45, CD56, FoxP3, and degranulation) and stimulation analysis 
via ICS of IFNγ and gzB 
 
Total PBMC counts by flow cytometry, including lymphocyte subsets (B cells, 
helper T-cells, cytotoxic T-cells, NK cells and T-reg)  
 
Evaluation of tumor tissue obtained prior to treatment for antigen expression, 
expression of major histocompatibility complex (MHC) class I, and expression of 
immunosuppressive molecules by mRNA expression and/or immunohistochemical 
analysis 
 
Evaluation of tumor tissue obtained from repeat biopsy, if clinically indicated, for 
presence of infiltrating T-lymphocytes (TILs) 
 
T cell receptor sequencing of PBMCs and tumor tissue to determine correlation 
between clonally expanded T cell populations and other endpoints 
 
Immune cell infiltration and inflammatory cytokine levels in urine (Phase 2 only) 

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Statistical methods: 
Patients will be randomized centrally using a stratified block design according to risk of 
recurrence (strata: high vs. intermediate risk) and CIS (strata: yes vs. no) for Arms 1-3.  
Patients who will not receive BCG will be consecutively allocated into a fourth arm 
consisting of vaccine monotherapy.  Efficacy comparisons between the monotherapy arm 
and any of the randomized arms will remain exploratory.  However, safety and point 
estimates with appropriate measures of variance (SD, 95% CI) for the efficacy parameters 
will be estimated. 
 
For the randomized portion, the sample size is based on the hypothesis that the addition of 
vesigenurtacel-L to BCG versus BCG alone will improve disease-free survival at one year.  
The sample size will be 75 patients randomized into two experimental groups consisting of 
BCG plus low dose vesigenurtacel-L (1 x 106 cells per dose) and BCG plus high dose 
vesigenurtacel-L (1 x 107 cells per dose) and to a control group consisting of BCG plus 
placebo (final allocation = 25 vs 25 vs. 25) to provide 46 events in the experimental groups 
and 23 events in the control group.  By assuming an alpha of 10% (one tailed), the 
randomized portion should have an 80% power to detect a 30% reduction in the risk of 
disease recurrence, progression, or death (control = 60% disease-free and alive vs. 90% in 
vesigenurtacel-L groups) at one year. There will be no adjustment for multiplicity in the 
comparison of the primary endpoint between the experimental groups and the control. 
 
The primary endpoint (proportion of patients alive and disease-free at one year) between 
the two experimental groups and the control will be compared using Fisher's exact test and 
presented as odds ratios (OR) with 95% confidence intervals (CI) relative to the control 
group.  ORs will be generated via a simple logistic regression model with one year disease-
free survival as the dependent variable and group as the sole independent variable (low dose 
and high dose vesigenurtacel-L vs. control).  If the analysis of the primary endpoint does 
not suggest any dose response effect between the two vaccine arms, an exploratory analysis 
will be conducted where the two vaccine arms will be pooled and compared to the control 
arm for the primary endpoint (proportion of patients alive and disease-free at one year).  The 
outcome will be presented as OR with 95% CI relative to the control group. 
 
Binary secondary endpoints will be presented as ORs with appropriate 95% CI.   
 
For the time to event endpoints (i.e. overall DFS and OS), survival curves will be generated 
by the method of Kaplan-Meier and compared with the log-rank test.  In an exploratory 
analysis, the weighted log rank test will also be used.  The weighted log rank preserves the 
statistical power that is lost due to the lag time effect in efficacy with immunotherapeutic 
agents.  In a supporting analysis, a simple Cox proportional hazards model with treatment 
group as the sole independent variable will be built in order to estimate the hazard rate (HR) 
and 95% CI for DFS between the low and high dose vesigenurtacel-L groups relative to the 
control. 
 
In an exploratory analysis, patients experiencing an immune response in all four treatment 
arms will be compared to those who did not experience an immune response.  The analysis 
will include a univariate comparison of patient and clinical variables at baseline 

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Statistical 
methods 
(con’t): 
as well as a comparison of any difference between immune responders and non-responders 
for the following endpoints: proportion with progressive or recurrent disease at selected 
time points, disease-free survival, proportion undergoing post-treatment TURBT or 
fulguration or cystectomy and overall survival. 
 
In an additional exploratory analysis, the proportion of patients whose disease has recurred 
to a lower stage than at screening and the proportion of patients whose disease has recurred 
to the same extent as at screening will be compared between the experimental and control 
groups at the 6, 12, 18, and 24 month time points and presented as an OR with 95% CI. 

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TABLE OF CONTENTS 
CLINICAL PROTOCOL SYNOPSIS ..........................................................................................................5 
TABLE OF CONTENTS ............................................................................................................................14 
LIST OF ABBREVIATIONS .....................................................................................................................18 
1.0 
BACKGROUND .............................................................................................................................20 
1.1 
Bladder Cancer ............................................................................................................................20 
1.2 
Rationale for Vesigenurtacel-L Development .............................................................................21 
1.3 
Description of Investigational Agent Vesigenurtacel-L ..............................................................22 
1.4 
Prior Human Experience .............................................................................................................23 
2.0 
OBJECTIVES .................................................................................................................................23 
2.1 
Primary Objective ........................................................................................................................23 
2.2 
Secondary Objectives ..................................................................................................................24 
2.3 
Exploratory Objectives ................................................................................................................24 
3.0 
TRIAL DESIGN ..............................................................................................................................24 
3.1 
Study Design Overview ...............................................................................................................24 
3.2 
Justification of Study Product Administration Strategy ..............................................................26 
3.3 
Number of Subjects .....................................................................................................................27 
3.4 
Study Endpoints ..........................................................................................................................27 
3.4.1 
Primary Efficacy Endpoint ..................................................................................................27 
3.4.2 
Secondary Endpoints ...........................................................................................................27 
3.4.3 
Exploratory Endpoints .........................................................................................................27 
3.5 
Study Termination Criteria ..........................................................................................................28 
4.0 
PARTICIPANT SELECTION ........................................................................................................28 
4.1 
Inclusion Criteria .........................................................................................................................28 
4.2 
Exclusion Criteria ........................................................................................................................29 
5.0 
SAFETY MONITORING ...............................................................................................................30 
5.1 
Data Monitoring Committee ........................................................................................................30 
5.1.1 
Phase 1 .................................................................................................................................30 
5.1.2 
Phase 2 .................................................................................................................................30 
5.2 
Dose Limiting Toxicities and Stopping Rules .............................................................................30 
5.2.1 
Dose Limiting Toxicities .....................................................................................................30 
5.2.2 
Trial Stopping Rules ............................................................................................................31 
5.3 
Emergency Unblinding of Treatment Assignment ......................................................................31 

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6.0 
STUDY PROCEDURES .................................................................................................................31 
6.1 
Phase 1 .........................................................................................................................................32 
6.1.1 
Phase 1 Schedule of Events .................................................................................................33 
6.1.2 
Phase 1 Screening Procedures .............................................................................................35 
6.1.3 
Phase 1 On-Study Procedures..............................................................................................35 
6.2 
Phase 2 .........................................................................................................................................38 
6.2.1 
Phase 2 Schedule of Events .................................................................................................39 
6.2.2 
Phase 2 Screening Procedures .............................................................................................41 
6.2.3 
Phase 2 On-Study Procedures..............................................................................................41 
6.3 
Long-term Follow-up Visits ........................................................................................................46 
6.4 
Blinding and Minimization of Bias .............................................................................................46 
7.0 
SUBJECT COMPLETION AND WITHDRAWAL .......................................................................47 
7.1 
Subject Completion .....................................................................................................................47 
7.2 
Subject Withdrawal from Study ..................................................................................................47 
7.2.1 
Discontinuation from Study Treatment ...............................................................................47 
7.2.2 
Discontinuation from Study Follow-Up ..............................................................................48 
7.2.3 
Lost to Follow-Up ...............................................................................................................48 
7.2.4 
Replacement of Subjects .....................................................................................................48 
8.0 
INVESTIGATIONAL PRODUCT .................................................................................................48 
8.1 
Description of Investigational Product, Vesigenurtacel-L ..........................................................48 
8.2 
Description of Placebo ................................................................................................................49 
8.3 
Dosage and Administration of Vesigenurtacel-L and Placebo ....................................................49 
8.4 
Dosage and Administration of BCG (Phase 2) ............................................................................49 
8.5 
Treatment Assignment.................................................................................................................49 
8.5.1 
Schedule and Duration of Treatment ...................................................................................50 
8.5.2 
Dose Modifications .............................................................................................................51 
8.6 
Study Product Handling and Accountability ...............................................................................51 
8.6.1 
Preparation ...........................................................................................................................51 
8.6.2 
Labeling ...............................................................................................................................51 
8.6.3 
Storage .................................................................................................................................51 
8.6.4 
Product Accountability ........................................................................................................51 
8.7 
Treatment of Investigational Product Overdose ..........................................................................52 
8.8 
Occupational Safety.....................................................................................................................52 

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9.0 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........................................52 
9.1 
Permitted Medications and Non-Drug Therapies ........................................................................52 
9.2 
Prohibited Medications and Non-Drug Therapies .......................................................................52 
9.3 
Supportive Care ...........................................................................................................................53 
10.0 
ASSESSMENT OF EFFICACY .....................................................................................................53 
10.1 
Evaluation of Disease ..................................................................................................................53 
10.2 
Immunologic Response ...............................................................................................................54 
10.2.1 
Production of Interferon-gamma from CD8+ T Cells (ICS Assay) ....................................54 
10.2.2 
PBMC Counts ......................................................................................................................55 
10.2.3 
Phenotyping of Blood Lymphocyte Subsets .......................................................................55 
10.2.4 
TCR Sequencing ..................................................................................................................56 
10.2.5 
Analysis of Infiltrating T Cells (Post-Treatment Tumor Biopsy)........................................56 
10.2.6 
Antigen Screening of Resected Tumor Tissue ....................................................................56 
11.0 
SAFETY ASSESSMENTS .............................................................................................................57 
11.1 
Physical Examination ..................................................................................................................57 
11.2 
Clinical Laboratory Tests ............................................................................................................57 
11.3 
Urinalysis .....................................................................................................................................58 
11.4 
ECG .............................................................................................................................................58 
11.5 
Autoimmune Monitoring .............................................................................................................58 
11.6 
Injection Site Reactions ...............................................................................................................58 
11.7 
Pregnancy ....................................................................................................................................58 
11.7.1 
Time Period for Collecting Pregnancy Information ............................................................58 
11.7.2 
Action to Be Taken if Pregnancy Occurs ............................................................................58 
11.7.3 
Action to be Taken if Pregnancy Occurs in a Female Partner of a Male Study Subject .....59 
11.8 
Adverse Events (AE) and Serious Adverse Events (SAE) ..........................................................59 
11.8.1 
Definition of an AE .............................................................................................................59 
11.8.2 
Definition of an SAE ...........................................................................................................60 
11.8.3 
Disease-Related Events or Outcomes Not Qualifying as SAEs ..........................................60 
11.8.4 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs .60 
11.8.5 
Reporting Adverse Events ...................................................................................................61 
11.8.6 
Prompt Reporting of SAEs ..................................................................................................61 
12.0 
STATISTICAL CONSIDERATIONS ............................................................................................63 
12.1 
General Statistical Considerations ...............................................................................................63 

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12.2 
Analysis Populations ...................................................................................................................64 
12.3 
Accountability, Demographics, and Baseline Characteristics .....................................................65 
12.4 
Safety Analysis ............................................................................................................................65 
12.4.1 
Adverse Events ....................................................................................................................65 
12.4.2 
Laboratory Assessments ......................................................................................................65 
12.4.3 
Vital Signs ...........................................................................................................................65 
12.4.4 
ECGs and Physical Examination .........................................................................................65 
12.4.5 
Other Assessments ...............................................................................................................66 
12.4.6 
Safety of Vesigenurtacel-L (Phase 1 and Arm 4 of Phase 2 Only) .....................................66 
12.4.7 
Safety of the Combination of Vesigenurtacel-L and BCG (Arms 1, 2, and 3 of Phase 2 
Only) 
 .............................................................................................................................................66 
12.5 
Efficacy Analysis (Phase 2) .........................................................................................................66 
12.5.1 
Primary Efficacy Analysis ...................................................................................................66 
12.5.2 
Analysis of Secondary Efficacy Parameters ........................................................................66 
12.6 
Sample Size Estimations .............................................................................................................68 
12.6.1 
Phase 1 .................................................................................................................................68 
12.6.2 
Phase 2 .................................................................................................................................68 
13.0 
STUDY CONDUCT CONSIDERATIONS ....................................................................................69 
13.1 
Regulatory and Ethical Considerations .......................................................................................69 
13.2 
Quality Control (Study Monitoring) ............................................................................................69 
13.3 
Protocol Deviations .....................................................................................................................69 
13.4 
Quality Assurance .......................................................................................................................70 
13.5 
Study and Site Closure ................................................................................................................70 
13.6 
Records Retention .......................................................................................................................70 
13.7 
Provision of Study Results and Information to Investigators ......................................................71 
13.8 
Data Management ........................................................................................................................71 
APPENDIX 1: BLADDER CANCER STAGING...................................................................................72 
APPENDIX 2: STAGES OF HEART FAILURE ....................................................................................73 
APPENDIX 3: GRADING SCALE FOR INJECTION SITE REACTIONS ..........................................74 
APPENDIX 4: PROTOCOL REVISION HISTORY ..............................................................................75 
REFERENCES ............................................................................................................................................85 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse event 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
AT 
As treated 
BCG 
Bacillus Calmette–Guérin  
cGMP 
current Good Manufacturing Practices 
CIS 
Carcinoma in situ 
CTCAE 
Common toxicity criteria for adverse events 
DMC 
Data Monitoring Committee 
DMSO 
Dimethyl sulfoxide 
ECG 
Electrocardiogram  
ECRF 
Electronic case report form 
ELISA 
Enzyme-linked immunosorbent assay 
EX 
Excluded subject 
EOT  
 
End of treatment 
ESR 
 
Erythrocyte sedimentation rate 
FACS  
Fluorescent-activated cell sorter 
FFPE  
Formalin-fixed, paraffin-embedded 
FDA 
 
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
gzB 
 
Granzyme B 
HIV 
 
Human immunodeficiency virus 
IEC 
 
Independent ethics committee 
IHC 
 
Immunohistochemistry 
IBC 
 
Institutional biosafety committee 
IBCG  
International Bladder Cancer Group 
ICS 
 
Intracellular cytokine staining 
IFNγ 
 
Interferon gamma 
IHC 
 
Immunohistochemistry 
IND 
 
Investigational New Drug (application) 
IRB 
 
Institutional Review Board 
ISR 
 
Injection site reaction 
ITT 
 
Intent to treat (population) 
MedDRA 
Medical dictionary for regulatory activities 
MHC  
Major histocompatibility complex 
NCI 
 
National Cancer Institute 
NED 
 
No evidence of disease 
NMIBC 
Non-muscle invasive bladder cancer 
NSCLC 
Non-small cell lung cancer 
NYHA  
New York Heart Association 
OS 
 
Overall survival 
PBMC  
Peripheral blood mononuclear cell 

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PCR 
 
Polymerase chain reaction 
PFS 
 
Progression free survival 
POC 
 
Proof of concept 
PP 
 
Per Protocol 
PT 
 
Preferred term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
 
Serious adverse event 
SAR 
 
Suspected adverse reaction 
SD 
 
Standard deviation 
SOE 
 
Schedule of events 
SOC 
 
Standard of care 
TCR 
 
T-cell receptor 
TURBT 
Transurethral resection of bladder tumor 
ULN 
 
Upper limits of normal 
WBC  
White blood cell 
 
 
 
 
 
 

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1.0 
BACKGROUND 
1.1 
Bladder Cancer 
Bladder cancer is the 6th most common cancer in the United States with an estimated 74,690 patients 
diagnosed in 2014 and 15,580 deaths. 1,2 Worldwide, 2.7 million people are living with a history of bladder 
cancer.2  Bladder cancer is estimated to be the most costly cancer in the US, and treatment-related 
complications are estimated to account for one-third of total costs.3,4 
Approximately 70-80% of patients have non-muscle invasive bladder cancer (NMIBC) at the time of 
diagnosis.5,6  Transurethral resection of bladder tumor (TURBT) is the standard treatment for NMIBC and 
aids in the proper diagnosis and staging of disease.   
Patients with low-risk disease (solitary, primary, low-grade, Ta tumors) have high recurrence-free and 
progression-free rates and an overall favorable prognosis.6,7  In contrast, patients with high-risk disease (T1 
and/or high grade and/or carcinoma in situ (CIS)) determined at the time of initial resection have a one year 
recurrence-free rate as low as 39%, and by five years, this rate has dropped even further to 20%.6   
Between these two extremes is a large group of patients classified as having intermediate-risk disease, 
which is defined as multiple or recurrent, low-grade, Ta tumors.7  Because this is a very broad spectrum of 
patients, the intermediate-risk category can be further stratified.  Intermediate-risk patients with at least 
three of the following four risk factors – multiple tumors, tumor size > 3cm, early recurrence (<1 year from 
previous TURBT), or frequent recurrences (i.e. recurrence with a frequency of more than once in any 12-
month period) – have treatment regimens and outcomes similar to high-risk patients, with recurrence-free 
rates of 62% at one year and 38% at five years.6,8  Patients with either high-risk disease or intermediate-risk 
disease with three or more risk factors will make up the patient population for this protocol. 
Adjuvant treatment options for patients with urinary bladder cancer are limited, as systemic chemotherapy 
appears largely ineffective in this setting.9,10  Adjuvant intravesical mitomycin-C, often given as a single 
dose within 24 hours of surgery, and intravesical bacillus Calmette-Guérin (BCG), which cannot be initiated 
until several weeks after surgery to reduce the risk of sepsis, have been used successfully to reduce local 
recurrence of NMIBC for over 30 years, but nearly a quarter of high-risk patients have evidence of disease 
6 months after induction BCG.11  Patients with intermediate- or high-risk disease benefit most when 
induction BCG is combined with a maintenance phase lasting at least one year.12,13,14,15  However, nearly 
15% of these patients will still go on to experience a recurrence after three years.15  Reasons for failure are 
not well defined but may be related to toxicities associated with these agents resulting in utilization of 
intravesical therapy well below recommended dose intensities.16,17  More recently, access to BCG, itself, 
has become a significant treatment barrier due to production problems with manufacturers of the drug. 
Because of the limited long term disease control possible with currently available adjuvant strategies in 
patients with high-risk NMIBC, the shortage of BCG, and the progressively less effective and more 
debilitating outcomes of subsequent rounds of surgical resection, there is a pressing need for alternate or 
complementary adjuvant strategies, such as vaccine-based immunotherapy, to reduce recurrence and 
improve tolerability of treatments in this patient group.  
Immunologic surveillance is the mechanism by which cells undergoing malignant transformation are 
eliminated from the body through recognition by innate and adaptive immune cells.  Immunotherapeutic 

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approaches designed to exogenously stimulate innate immune surveillance can be classified broadly under 
active 
immunotherapy/therapeutic 
vaccines, 
adoptive 
cellular 
immunotherapy, 
and 
passive 
immunotherapy.18  Although most clinically advanced cancers have escaped immunological control 
mechanisms, the possibility that autologous cellular immunity can be restimulated to target cancer cells has 
led to a number of therapeutic trials of a variety of immunotherapy approaches.19  These studies have 
demonstrated that improved overall survival can be achieved even in generally chemoresistant 
malignancies, such as advanced renal cancer, prostate cancer, and melanoma.19,20,21,22  Immunomodulation 
is particularly appropriate in the context of minimal residual disease, such as immediately after TURBT, 
since it is believed that it may be the setting in which this approach is most effective.23 
Recent advances in the immunotherapy field have led to the understanding that destruction of a tumor 
involves multiple coordinated immune mechanisms, including activation of antigen presenting cells and 
effector T cells, blockade of immune regulatory molecules, including CTLA-4 and PD-1, and reduction of 
suppressor T cells.24  Additionally, it is now recognized that immunotherapeutic agents are frequently 
characterized by a period of latency between administration and subsequent clinical response, which is in 
contrast to traditional chemotherapeutic or small molecule regimens wherein the clinical response is 
predicted by and associated with the peak concentration of drug achieved shortly after administration.  
Furthermore, shortly after initiating immunotherapy treatment, patients may appear to experience disease 
progression as assessed by conventional imaging techniques, before the onset of biological activity and 
clinical effect.25   
Greater understanding of the methodological complexity of assessing immunotherapeutic agents are now 
resulting in more appropriate clinical trial designs, which have significantly improved the probability of 
detecting the anti-cancer clinical utility of immunotherapeutic approaches in early stage clinical trials, such 
as the one described in this protocol. 
1.2 
Rationale for Vesigenurtacel-L Development 
The hypotheses behind the development of vesigenurtacel-L (HS-410), a therapeutic vaccine, to treat 
urothelial cancer of the bladder are as follows:   
(1) A range of tumor-associated antigens (survivin, LAGE-1, MAGE-A3, MAGE-A11, and 
PRAME) have been identified in bladder cancer, and it is postulated that treatment with BCG 
therapy provides the innate immune system with a warning signal to induce and direct an acquired 
immune response against such antigens.26  However, BCG therapy is accompanied by a high failure 
rate and significant side effects, which limit its clinical application.  The clinical response to BCG 
might be improved through concurrent enhancement of tumor immunogenicity by concomitant 
administration of a vaccine, such as vesigenurtacel-L, during standard BCG therapy.   
(2) Secreted gp96-Ig from vesigenurtacel-L combines adjuvant activity with polyvalent peptide 
specificity.  Vesigenurtacel-L activates dendritic cells (DC), natural killer (NK) cells, and cytotoxic 
T lymphocytes (CTL).  Tumor cells can be killed by NK cell-specific mechanisms, by promiscuous 
killing by CD8+ CTL through NKG2D, and by major histocompatibility complex (MHC)-restricted 
CD8+ CTL activity.  The activation of DC and NK cells by vesigenurtacel-L may also counteract 
the generation of immunosuppressive CD4+ regulatory cells. 

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(3) Vesigenurtacel-L also stimulates antigen cross presentation via the CD91 receptor, Toll-like 
receptor (TLR) 2 and TLR4 on DC and macrophages.  Allogeneic tumor cells are likely to share 
public tumor antigens in analogy to melanoma.  Therefore, allogeneic, gp96-secreting tumor cells 
used as a vaccine (such as vesigenurtacel-L) are expected to generate NK cell and CTL activity to 
the patient’s autologous tumor. 
(4) BCG activates innate immune receptors, primarily TLR, within the endothelial lining of the 
bladder following intravesical administration.  Activation of these innate receptors contributes to 
the local production of inflammatory cytokines, including IL-1β and TNFα, which provide an 
inflammatory signal leading to upregulation of the local microvascular endothelium within the 
bladder wall, including expression of selectin ligands and integrins, such as ICAM-1 and VCAM-1. 
Vesigenurtacel-L is administered intradermally and leads to the activation of antigen-specific 
CD8+ T cells that circulate through the systemic vasculature.  Extravasation of T cells into tissues 
requires activation of endothelial cells, and trafficking through inflamed vessels is mediated by 
selectins, integrins, and chemokines.  Thus, the systemic activation of T cells by vesigenurtacel-L 
is proposed to synergize with BCG through the combined increase in bladder-tumor antigen-
specific T cells that may traffic more efficiently into the bladder due to endothelial activation by 
locally administered BCG. 
Similarly, inflammation generated in response to the TURBT surgical procedure may drive CD8+ 
T cells into the bladder tissue, even in the absence of BCG, mediating CD8+ T cell trafficking to 
the bladder in a BCG-independent fashion.  Initiating vaccination during the perioperative period 
immediately after TURBT potentially capitalizes on this period of post-operative immunoactivity. 
(5) In current clinical practice, no treatment is typically administered during the 6 week period 
following completion of BCG induction therapy and prior to the next cystoscopy.  Continued 
treatment with a vaccine, such as vesigenurtacel-L, during this time may provide an additional 
important window for continued immune stimulation, which could result in improved treatment 
response.   
(6) Although it is postulated that concurrent administration of intravesical BCG and intradermal 
vesigenurtacel-L might result in optimally synergistic immunoactivation, it is also possible that 
intradermal vesigenurtacel-L monotherapy will result in a significant degree of immune 
modulation, independently of concomitant BCG. The current study will, therefore, examine 
vesigenurtacel monotherapy in patients who will not receive BCG. 
1.3 
Description of Investigational Agent Vesigenurtacel-L 
Vesigenurtacel-L is a whole cell vaccine that has been irradiated to render cell replication incompetent 
while maintaining biological activity, i.e., expression of certain tumor-associated antigens as described 
above. 
Vesigenurtacel-L is derived from a human prostate cancer cell line, PC3.   This cell line was evaluated 
amongst others and was selected based on the overlap of its native antigenic profile with that of tumor 

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samples from patients with NMIBC. The chosen PC3 tumor cells were modified to express HLA-A1 
protein and secrete gp96-Ig fusion protein by stable transfection.  Clones with a high level of expression 
were obtained by G418 (Geneticin) selection and flow cytometry cell sorting. 
Preparation of the drug product includes expansion of batches of cells using current good manufacturing 
practices (cGMP) manufacturing methods.  The cells are tested for presence of expression of HLA-A1 by 
fluorescent-activated cell sorter (FACS) and gp96-Ig expression by enzyme-linked immunosorbent assay 
(ELISA).  Cells are harvested, washed, resuspended in buffered saline, irradiated, washed and vialed.  The 
vialed cells are frozen and then stored at ≤ -120C in the vapor phase of a liquid nitrogen freezer. 
1.4 
Prior Human Experience 
This is the first trial to dose patients with vesigenurtacel-L.  A first-in-human Phase 1 study of HS-110, a 
lung cancer vaccine using the same technology platform, was conducted in 18 patients with advanced non-
small cell lung cancer (NSCLC).27  Patients received one of three dosing regimens.  Safety was evaluated 
as a primary endpoint and tumor response and survival were secondary endpoints.  Immune response in 
peripheral blood was characterized in 15 patients who received at least one course (6 weeks) of vaccination 
by measuring production of IFN-γ by patient CD8+ T cells as compared to baseline.  
The majority of adverse events were mild injection site reactions, consisting mainly of rash, induration, 
pruritus, and pain.  Six serious adverse events were reported for five patients: respiratory disorder for a 
patient who was enrolled but not treated with HS-110, disease progression (two patients), chest pain, and 
dyspnea and rectal hemorrhage.  None of these events was considered by the investigator to be treatment-
related.  
None of the 18 patients had an objective tumor response by the Response Evaluation Criteria in Solid 
Tumors (RECIST).  Fourteen patients had died, and four surviving patients were followed for a median of 
10.6 months (range 2.6 to 16.6).  The Kaplan-Meier estimate of median survival was 8.0 months (95% 
confidence interval [CI]: 6.7 to 18.2), and the 6, 12, and 24-month overall survival (OS) rates were 77.8% 
(95% CI: 51.1 to 91.0%), 41.9% (95% CI: 19.1 to 63.3%), and 11.2% (95% CI: 0.8 to 37.3%), respectively.  
All patients have now died. 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
Phase 1  
To characterize the safety and tolerability of low dose monotherapy vaccination with vesigenurtacel-L in 
patients with non-muscle invasive bladder cancer  
 
Phase 2 
 
Arms 1, 2, and 3: To evaluate 1-year disease-free survival in patients with non-muscle invasive 
bladder cancer treated with BCG in combination with blinded study product (one of two doses of 
vesigenurtacel-L or placebo) 
 
Arm 4: To evaluate 1-year disease-free survival in patients with non-muscle invasive bladder 
cancer treated with high dose vesigenurtacel-L monotherapy 

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2.2 
Secondary Objectives 
 To evaluate the safety of the combination of vesigenurtacel-L and BCG (Phase 2 only) 
 To evaluate the safety of high dose vesigenurtacel-L monotherapy (Phase 2 only) 
 To evaluate the proportion of patients with recurrence at 3, 6, 12, 18, and 24 months 
 To evaluate the proportion of patients with progressive disease at 3, 6, 12, 18, and 24 months 
 To evaluate disease-free survival at 3, 6, 18, and 24 months 
 To evaluate overall disease-free survival 
 To evaluate overall survival (OS) 
 To evaluate the proportion of patients undergoing post-treatment TURBT or fulguration by 12 and 24 
months 
 To evaluate the proportion of patients undergoing cystectomy by 12 and 24 months  
 To evaluate the proportion of patients with immunologic response of PBMCs via intracellular cytokine 
staining (ICS) by flow cytometry and/or ELISPOT on CD8+ cells following vesigenurtacel-L 
vaccination  
2.3 
Exploratory Objectives 
 
Immunologic response of PBMCs (analysis of surface markers, CD3, CD4, CD8, CD19, CD25, 
CD45, CD56, FoxP3, and degranulation) and stimulation analysis via ICS of IFNγ and granzyme 
B (gzB)  
 
Total PBMC counts by flow cytometry, including lymphocyte subsets (B cells, helper T-cells, 
cytotoxic T-cells, NK cells and T-reg)  
 
Evaluation of tumor tissue obtained prior to treatment for antigen expression, expression of major 
histocompatibility complex (MHC) class I, and expression of immunosuppressive molecules 
 
Evaluation of tumor tissue obtained from repeat biopsy, if clinically indicated, for presence of 
tumor infiltrating T-lymphocytes (TILs) 
 
T cell receptor sequencing of PBMCs and tumor tissue to determine correlation between clonally 
expanded T cell populations and other endpoints 
 
Immune cell infiltration and inflammatory cytokine levels in urine (Phase 2 only) 
3.0 
TRIAL DESIGN 
3.1 
Study Design Overview 
This is a multi-center, randomized, placebo-controlled study consisting of two phases as shown in Figure 1 
below. 

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Figure 1. Study Design 
 
Patients with non-muscle invasive bladder cancer who have either undergone TURBT or fulguration for 
the removal of papillary disease or who have carcinoma in situ (CIS) only, are candidates for BCG 
treatment, and are judged to be at an increased risk for recurrence are eligible if they are BCG naive or have 
completed previous BCG treatment >12 months prior to the baseline staging procedure.  Phase 2 also allows 
patients who will not otherwise receive BCG. 
The Phase 1 portion is an open-label, safety study consisting of one cohort with 10 patients.  Patients will 
have previously received 3-6 instillations of weekly intravesical BCG induction therapy (as standard of 
care) followed by low dose intradermal (1 x 106 cells) vesigenurtacel-L monotherapy.  
In Phase 2, patients will be assigned to treatment groups based on whether they will receive induction BCG 
in the typical post-TURBT window.  If the investigator plans to administer BCG, patients will be 
randomized to one of three blinded (physician-patient), placebo-controlled groups and receive either 
intradermal placebo or low dose or high dose (1 x 107 cells) vesigenurtacel-L in combination with induction 
and maintenance intravesical BCG.  If patients will not receive BCG, they will be enrolled into an open-
label, non-randomized group and receive high dose intradermal vesigenurtacel-L monotherapy. 
Phase 1: Patients enrolled in the first cohort within 8-10 weeks of TURBT or fulguration for patients with 
papillary disease and staging procedure for patients with CIS only and after induction BCG will be treated 
with vesigenurtacel-L weekly for 6 weeks.  After a one-week vaccine holiday for disease assessment, 
patients will receive vesigenurtacel-L for an additional 6 weeks followed by three once monthly treatments 
for a total of 15 vaccinations.  Patients will be observed weekly to assess the safety of vesigenurtacel-L.  
Dosing of the first three patients will be staggered by two-week intervals to allow for safety evaluation 
before treating additional patients.  If vesigenurtacel-L appears safe and well-tolerated in the 3 lead-in 
patients, dosing will be continued to 10 patients.   

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Phase 2: Dosing in Phase 2 will begin when all 10 patients have been dosed in the Phase 1 cohort, at least 
6 patients in that cohort have completed the Week 7 safety assessments, and the Data Monitoring 
Committee (DMC) has met to review this data and agreed it is safe to advance to Phase 2.  A total of 100 
patients will be assigned to four groups: 75 who will receive BCG will be randomized to arms combining 
either low dose vesigenurtacel-L, high dose vesigenurtacel-L, or placebo, respectively, with induction and 
maintenance BCG; 25 who will not receive BCG will be enrolled in the high dose vesigenurtacel-L 
monotherapy arm.  
In the randomized arms, treatment will commence within 6 weeks of the most-recent TURBT or fulguration 
for patients with papillary disease and staging procedure for patients with CIS only.  Patients will be treated 
during an induction phase with weekly intravesical BCG and intradermal blinded study product 
(vesigenurtacel-L or placebo) for 6 weeks followed by 6 weekly injections of blinded study product alone.  
During a subsequent maintenance phase, patients will receive an additional three courses of three once-
weekly blinded study product injections in combination with intravesical BCG approximately 3, 6, and 12 
months after initiating induction BCG.  Patients may receive additional courses of maintenance BCG in 
long-term follow-up at the investigator’s discretion but should not receive any other cancer therapy prior to 
disease recurrence/progression. 
In the monotherapy arm, treatment will commence within 6 weeks of the most-recent TURBT or fulguration 
for patients with papillary disease and staging procedure for patients with CIS only.  Patients will be treated 
during an induction phase with weekly intradermal vesigenurtacel-L for 12 weeks.  During a subsequent 
maintenance phase, patients will receive an additional three courses of three once-weekly vesigenurtacel-L 
injections approximately 3, 6, and 12 months after initiating induction vesigenurtacel-L.   
All patients in both the Phase 1 and Phase 2 portions of the study will have a cystoscopy and cytology and, 
if clinically indicated, a biopsy performed approximately every 3 months for 2 years then every 6 months 
for up to a year, study termination, disease progression, or recurrence requiring treatment discontinuation, 
whichever occurs first.  Patients with evidence of disease at an assessment may continue on treatment if 
judged by the investigator to be in the patient’s best interest (e.g. would normally receive another course of 
BCG therapy as standard of care (SOC)). Upon discontinuation of study treatment, additional treatment 
will be at the discretion of the treating physician per SOC. While treatment may continue in the presence 
of evidence of disease, statistical analysis of disease-free status will still follow strict definitions as defined 
in section 10.1 Evaluation of Disease. 
3.2 
Justification of Study Product Administration Strategy 
A clinical trial of a similar vaccine for lung cancer derived from the same proprietary technology as the 
vaccine for this study examined three dosing schedules: twice weekly, weekly, and once every two weeks. 
The twice weekly and weekly dosing schedules were determined to produce the most desirable immune 
response in peripheral blood (at least a doubling of CD8 from baseline).  The weekly dosing schedule was 
selected for this trial as it was determined to provide reasonable patient acceptability for frequency of 
treatment visits and concordance with the standard BCG dosing schedule. 
Two doses were selected (1 x 106 cells and 1 x 107 cells) for this study.  The 1 x 107 cell dose was selected 
based on the number of cells needed to produce an equivalent amount of gp96-Ig to that used in the lung 
cancer vaccine.  Additionally, murine data suggest that lower doses may produce a sufficient immune 

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response and may even result in superior clinical effects, and therefore, the lower dose of 1 x 106 cells was 
included as one of the two doses for evaluation in this trial. 
Study product will be administered weekly as the number of intradermal injections required to reach the 
number of cells per dose with no more than 0.1mL per injection (see Section 8.3).  The selection of the 
route of administration is based on the hypothesis that split doses stimulate stronger immune responses by 
allowing vaccine antigens to reach more regional lymph nodes (where immune responses are generated).  
Vesigenurtacel-L will be administered intradermally to enhance stimulation of cellular immune responses 
as compared to subcutaneous or intramuscular immunization. 
3.3 
Number of Subjects 
Approximately 110 patients will be enrolled from up to 20 clinical trial centers.  In Phase 1, 10 patients will 
be enrolled in a single cohort given treatment with monotherapy low dose vesigenurtacel-L.  In Phase 2, 25 
patients will be enrolled in each of four arms: low dose vesigenurtacel-L in combination with BCG, high 
dose vesigenurtacel-L in combination with BCG, placebo in combination with BCG, and high dose 
vesigenurtacel-L monotherapy (100 patients total). 
3.4 
Study Endpoints 
3.4.1 
Primary Efficacy Endpoint 
Phase 1: 
Safety and tolerability 
Phase 2: 
1-year Disease-Free Survival (1-yr DFS) 
3.4.2 
Secondary Endpoints 
 
Safety of the combination of vesigenurtacel-L and BCG (Phase 2 only) 
 
Safety of high dose vesigenurtacel-L monotherapy (Phase 2 only) 
 
Proportion of patients with recurrence at 3, 6, 12, 18, and 24 months 
 
Proportion of patients with progressive disease at 3, 6, 12, 18 and 24 months 
 
Disease-free survival (DFS) at 3, 6, 18, and 24 months 
 
Overall DFS 
 
Overall Survival (OS) 
 
Proportion of patients undergoing post-treatment TURBT or fulguration by 12 and 24 months 
 
Proportion of patients undergoing cystectomy by 12 and 24 months 
 
Proportion of patients with immunologic response of PBMCs via intracellular cytokine staining 
(ICS) by flow cytometry and/or ELISPOT on CD8+ cells after receiving vesigenurtacel-L 
treatment as compared to baseline 
3.4.3 
Exploratory Endpoints 
 
Immunologic response of PBMCs (analysis of surface markers, CD3, CD4, CD8, CD19, CD25, 
CD45, CD56, FoxP3, and degranulation) and stimulation analysis via ICS of IFNγ and gzB 
 
Total PBMC counts by flow cytometry, including lymphocyte subsets (B cells, helper T-cells, 
cytotoxic T-cells, NK cells and T-reg) 

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 
Evaluation of tumor tissue obtained prior to treatment for antigen expression, expression of major 
histocompatibility complex (MHC) class I, and expression of immunosuppressive molecules by 
mRNA expression and/or immunohistochemical analysis 
 
Evaluation of tumor tissue obtained from repeat biopsy, if clinically indicated, for presence of 
infiltrating T-lymphocytes (TILs) 
 
T cell receptor sequencing of PBMCs and tumor tissue to determine correlation between clonally 
expanded T cell populations and other endpoints 
 
Immune cell infiltration and inflammatory cytokine levels in urine (Phase 2 only) 
3.5 
Study Termination Criteria 
The sponsor may terminate the study at any time on the basis of safety considerations or other factors that 
may be deemed to affect the scientific validity or ethical viability of the protocol. 
4.0 
PARTICIPANT SELECTION 
4.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be enrolled into the study: 
1. Willing and able to sign informed consent and comply with the protocol, including clinic visits to 
receive weekly vesigenurtacel-L injections for 12 doses followed by either monthly vesigenurtacel-
L injections for three months in Phase 1 or three courses of three once-weekly injections in Phase 
2. 
2. Histologically or cytologically confirmed non-muscle invasive bladder cancer [Ta, T1 or Tis 
(CIS)].  Papillary disease must have been removed by transurethral resection or fulguration. 
3. Either  
i. 
High-risk disease, defined as T1 and/or high-grade and/or CIS, or 
ii. 
Intermediate-risk disease defined as Ta low-grade with at least three of the following four 
risk factors: multiple tumors, tumor size > 3cm, early recurrence (<1 year from previous 
staging procedure), or recurrence with a frequency of more than once in any 12 month period. 
4. Patients must be BCG naive or have completed previous BCG treatment >12 months prior to the 
baseline staging procedure. 
5. 
For Phase 2 only: Arms 1, 2, and 3: Suitable, in the opinion of the investigator, to receive a 6-week 
course of induction intravesical BCG in the adjuvant setting within 6 weeks following the baseline 
staging procedure for the current occurrence of non-muscle invasive bladder cancer.  Arm 4: 
Suitable for monotherapy vaccine administration post-TURBT.  For Phase 1 only: Has previously 
received 3-6 weekly doses of BCG. 
6. Age ≥18 years 
7. Lab parameters:  

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 
Albumin ≥2.5 mg/dL  
 
Total bilirubin <1.5 mg/dL  
 
Alanine transaminase (ALT) and aspartate transaminase (AST) ≤2.5 × upper limit of normal 
(ULN) 
 
Serum creatinine ≤2.2 mg/dL or calculated creatinine clearance >35 mL/minute per the 
Cockcroft-Gault formula 
 
White blood cell (WBC) count ≥4,000/mm3 with an absolute neutrophil count ≥1,500/mm3 
 
Hemoglobin ≥9 g/dL   
 
Platelet count ≥75,000/mm3 
8. Women of childbearing potential or men of fathering potential must use adequate birth control 
measures (e.g., abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, 
or surgical sterilization) during the study and for 6 months after receiving the last administration of 
study medication.  Female patients of childbearing potential must test negative for pregnancy prior 
to enrolling in the trial.  
4.2 
Exclusion Criteria 
Patients that meet any of the following exclusion criteria are not eligible to be enrolled into the study: 
1. Known human immunodeficiency virus (HIV) infection or other immunodeficiency disorders, 
either primary or acquired 
2. Infections or concurrent illness, requiring active therapy 
3. Any condition requiring active steroid or other immunosuppressive therapy 
4. Active malignancies within 12 months with the exception of those with a negligible risk of 
metastasis or death treated with expected curative outcome 
5. Prior prostatic pelvic radiation within the past 12 months 
6. Known history of clinically significant cardiac impairment, congestive heart failure > New York 
Heart Association (NYHA) cardiac disease classification Class II, unstable angina, or myocardial 
infarction during the previous three months 
7. Known current alcohol or chemical abuse, or mental or psychiatric condition precluding 
compliance with the protocol 
8. Pregnant or nursing 
9. Known allergy to soy, egg, or peanut products 
10. Receiving another investigational agent (30 day wash-out required prior to first dose) 
11. Neo-adjuvant therapy prior to the baseline staging procedure for the current occurrence of non-
muscle invasive bladder cancer 
12. Prior treatment with a cancer vaccine for this indication 

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13. Prior vaccination with BCG for tuberculosis disease 
14. Prior splenectomy 
5.0 
SAFETY MONITORING 
5.1 
Data Monitoring Committee 
A study specific Data Monitoring Committee (DMC) will provide dose expansion recommendations during 
Phase 1 and will continue safety surveillance in Phase 2.  A full description of the membership, role, and 
responsibilities of the DMC will be outlined in a separate charter. 
5.1.1 
Phase 1 
A lead-in phase will enroll three patients in Phase 1 at the low dose of vesigenurtacel-L (1 x 106 cells).  
Patients will be observed weekly to assess the safety of vesigenurtacel-L.  Dosing of the first three patients 
will be staggered by two-week intervals to allow for safety evaluation before treating additional patients.  
The DMC will convene after the third patient has received at least two doses of vesigenurtacel-L and at 
least one patient has completed the Week 7 safety assessments.  If vesigenurtacel-L appears safe and well-
tolerated in the 3 lead-in patients, dosing will be continued to 10 patients.  
The DMC will reconvene when all 10 patients in Phase 1 have received vesigenurtacel-L and data is 
available for the Week 7 safety assessments from at least 6 patients. If this regimen is determined to be safe 
by the DMC, Phase 2 will commence. 
5.1.2 
Phase 2 
In order to continually monitor safety during the Phase 2 portion, the DMC will review (unblinded) all 
available safety data after one patient has been randomized to each of the active arms and has completed 
four weeks of treatment and then after 3, 6, and 12 patients in each randomized treatment group have 
completed the Week 7 assessment.  Subsequently the DMC will review all available safety data at regular 
three-monthly intervals until study completion or should they determine that review is no longer necessary.  
Additionally, the DMC will convene on an ad-hoc basis should any patient experience a Grade 3 or higher 
adverse event (considered by the investigator to be related to vesigenurtacel-L) at any time during the study.  
Depending on emerging data, the DMC will have the authority to suspend allocation to a particular study 
treatment and require that additional patients are studied in a particular arm or at a particular dose level of 
vesigenurtacel-L, in order to further characterize the safety profile. 
5.2 
Dose Limiting Toxicities and Stopping Rules 
5.2.1 
Dose Limiting Toxicities 
Dose limiting toxicities (DLT) (i.e. toxicities which would prevent an escalation to a higher dose in Phase 2) 
will be evaluated by the DMC during Phase 1 of the trial. The period for evaluating DLTs will be from the 
time of administration of the first dose of vesigenurtacel-L until the time that all 10 patients in Phase 1 have 
received at least one dose of vesigenurtacel-L and at least 6 patients have received 6 doses.  A DLT is 

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defined as any anaphylactic reactions, a full-thickness ulceration/necrosis, or any AE ≥ Grade 3 related to 
study product with the following exceptions:  
 
Local injection site reactions lasting <72 hours including pain, redness, swelling, induration, or 
pruritus 
 
Systemic reactions lasting <72 hours of fever, myalgia, headache, or fatigue 
Grading of DLTs will be according to the National Cancer Institute (NCI) Common Toxicity Criteria for 
Adverse Event (CTCAE) v 4.03. 
If one patient in Phase 1 experiences a DLT prior to the dose expansion decision to move to Phase 2, 
escalation may still be considered; if more than one patient experiences a DLT , expansion will not occur. 
5.2.2 
Trial Stopping Rules 
In the event of a death within 24 hours of vaccination that cannot be clearly attributed to another cause, or 
≥3 related SAEs (in any number of patients) at any time after receiving study product during the treatment 
period, dosing will halt immediately, and the DMC will be consulted.  All data will be reviewed prior to 
any further dosing, and dosing will not continue until the DMC agrees that it is safe to continue.  At the 
discretion of the DMC, the Food and Drug Administration (FDA) or other Health Regulatory Agencies may 
be consulted. 
5.3 
Emergency Unblinding of Treatment Assignment  
Investigational product for this study has been packaged and labeled in a blinded fashion.  Although the 
vial labels will be blinded in Phase 1 of the trial, the patient and the study personnel will know the dose the 
patient is receiving, since the Phase 1 portion of the trial is not blinded.  For the Phase 2 portion of the trial, 
patients in Arms 1-3 will be randomized to vesigenurtacel-L (high dose or low dose) or placebo.  The patient 
and site personnel will not know which treatment the patient is receiving.  For Arm 4, however, patients 
and study personnel will know the treatment the patient is receiving. 
Unblinding a treatment assignment for adverse events should only be performed in situations where 
knowledge of the treatment assignment is essential for further medical management of the patient.  
Unblinding can only be done by the study medical monitor.  When unblinding is necessary, the investigator 
should contact the study medical monitor to discuss.  All unblinding events will be recorded and reported 
by the IWRS.  Specific steps for requesting unblinding will be provided in the Study Procedures Manual.  
6.0 
STUDY PROCEDURES 
A signed, written informed consent form that is currently approved by an IRB must be obtained from the 
potential patient before he/she can participate in any study-specific procedures, including screening 
procedures. 
Patients will be enrolled (Phase 1 and Arm 4 of Phase 2) and randomized (Arms 1-3 of Phase 2) once all 
screening procedures have been completed and it is determined that the patient meets all eligibility 
criteria.  The schedule of assessments is distinct for patients receiving low dose vesigenurtacel-L 
monotherapy in Phase 1 and for patients receiving blinded study product (vesigenurtacel-L or placebo) in 

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combination with BCG or high dose vesigenurtacel-L monotherapy in Phase 2. These two different 
schedules are outlined below. 
6.1 
Phase 1 
 
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6.1.1 
Phase 1 Schedule of Events 
1 Screening evaluations should be completed ≤2 weeks of first dose.   
2 PE, hematology, chemistry, LDH, dipstick urinalysis and pregnancy test do not need to be repeated at Baseline if they were performed at Screening within three days prior to first 
dose. 
3 First vesigenurtacel-L dose should occur 8-12 weeks (56-84 days) following TURBT or fulguration for patients with papillary disease and staging procedure for patients with CIS 
only regardless of the number of BCG instillations.  
4 Weekly study evaluations should be completed within ±1 day of the target visit date.  
5  EOT evaluations should be completed 4 weeks ±3 days after last dose of study vesigenurtacel-L or early discontinuation of study treatment. 
6  PE at screening and Week 29 (End of Treatment) will have a full examination of body systems and vital signs. Other PE evaluations will be limited to symptoms, weight and vital 
signs. 
Procedure 
Screening Baseline 
  
Week 
13 
Weeks 
2-64 
Week 
7 
Weeks 
8-134 
Week 
14 
Week  
17  
Week 
21 
Week 
25 
Week 29 
(EOT)5 
Long-term 
Follow-up 
Study Day 
≤ -4 wks. 
-3 to 1   
1 
 
43 (±1)  
92 (±1) 113 (±3) 141 (±3) 169 (±3) 197 (±3) Q3mos. 2 yrs; 
Q6mos. 3rd yr 
Baseline Documentation 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Verify All Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X1 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam6 
X 
X2 
 
 
X 
 
X 
 
 
 
X 
 
Pathology Review 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
Laboratory Studies 
 
 
 
 
 
 
 
 
 
 
 
 
Immunologic Response7 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
Hematology, Chemistry and LDH, Dipstick Urinalysis 
X1 
X2 
 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy Test (urine or serum) 
X1 
X2 
 
 
 
 
 
 
 
 
X 
 
Autoimmune Labs8 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Tumor Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Cystoscopy/Cytology for disease recurrence per SOC9 
 
 
 
 
X 
 
 
 
X 
 
 
X13  
Tumor collection for antigen screen 
 
 
X 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
 
 
Vesigenurtacel-L Administration10 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
 
Other Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Autoimmune Phenomena11 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Adverse Events12 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X1 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival and subsequent therapy 
 
 
 
 
 
 
 
 
 
 
 
X 

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7 70mL of heparinized blood and 10mL of non-heparinized blood will be collected at the indicated visits. 
8 ANA, TSH, ESR, C-reactive protein are required. Other tests (e.g. RF, T3, T4, thyroid antibodies) will be performed only as clinically indicated. 
9 All patients will have a cystoscopy/cytology performed at Week 7 and at Week 21. If clinically indicated, a repeat biopsy will be performed.  Patients with evidence of disease at 
an assessment may continue on treatment if judged by the investigator to be in the patient’s best interest (e.g. would normally receive another course of BCG therapy as SOC).  
Upon discontinuation of study treatment, additional treatment will be at the discretion of the treating physician, and patients will continue in long-term follow-up on the study.  
10 Vesigenurtacel-L is administered weekly x 6 weeks to all patients. Patients continuing on trial will receive 6 additional weekly vaccinations then monthly x 3 months. Each dose 
will be divided into the number of intradermal injections required to reach 1x106 cells per dose with no more than 0.1 mL per injection (approximately 4-6 injections). Patients 
should remain on site for 30 minutes following each vaccination for observation of adverse events. 
11 Includes eye exam for dry eyes, lymph node and joint assessment, and skin exam for vitiligo and rashes. 
12  AEs should be recorded from first dose through four weeks following the last dose of study medication regardless of the causal relationship to the study medication.  AEs considered 
related to study medication should be recorded at any time regardless of when they occurred.  
13 Cystoscopy/Cytology for disease recurrence per SOC (approximately every 3 months for 2 years then every 6 months for up to a year).  Patients who are determined to have 
evidence of disease will have SOC treatment per the discretion of the investigator and will continue in long-term follow-up on the study. 
 

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6.1.2 
Phase 1 Screening Procedures 
The following procedures must be conducted ≤4 weeks prior to the first dose of vesigenurtacel-L: 
 
Written informed consent 
 
Verify eligibility criteria 
 
Patient demographics 
 
Pathology Review 
o Verification of Bladder Cancer Staging at the time of the most recent staging procedure 
(refer to Appendix 1.)  High-risk or intermediate-risk non-muscle invasive disease must be 
histologically/cytologically confirmed.  There will be no central pathology review.  In the 
event that multiple procedures are performed for this occurrence of disease, dates of all 
procedures will be captured. 
o Verification of documentation of cancer sub-type (transitional cell carcinoma, squamous 
cell carcinoma, adenocarcinoma or undifferentiated carcinoma) 
 
Physical examination (including weight, vital signs [heart rate, temperature, respiratory rate and 
blood pressure]) 
 
12-lead electrocardiogram (ECG) 
The following procedures must be conducted ≤2 weeks prior to the first dose of vesigenurtacel-L: 
 
Medical history, including concomitant medications within 14 days of first dose 
 
Hematology, chemistry with LDH, and dipstick urinalysis 
 
Urine or serum pregnancy test for female patients of childbearing potential  
6.1.3 
Phase 1 On-Study Procedures 
Study-related procedures and assessments performed during treatment on study are detailed as follows and 
in the Schedule of Events table (see Section 6.1.1).   
6.1.3.1 Phase 1 Baseline Assessments (Day -3 to Day 1) 
The following activities may be performed within three days of enrollment or on Day 1 prior to dosing: 
 
Update of medical history, including concomitant medications 
 
Blood draw for immune monitoring 
 
Physical examination (symptoms, weight, vital signs only if screening exam performed more than 
three days prior to first dose) 
 
Hematology, serum chemistry, urinalysis (unless screening labs obtained within three days of first 
dose) 
 
Urine or serum pregnancy test for female patients of childbearing potential (unless screening labs 
obtained within three days of first dose) 
 
Autoimmune Labs (ANA, TSH, ESR, and C-reactive protein are required; RF, T3, T4, and thyroid 
antibodies if clinically indicated) 
 
Assessment of adult autoimmune system disorders (including: eye exam for dry eyes, lymph node 
and joint assessment for swelling, and skin exam for vitiligo and rash) 

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Once the patient has met all of the eligibility requirements for the study, the patient will receive the 
treatment assignment from IWRS.  Each patient will be considered enrolled in the study at the time of 
treatment assignment. 
6.1.3.2 Phase 1 Assessments at Week 1 (Day 1)  
The following procedures will be performed after all the previous baseline procedures have been completed. 
 
Study product administration  
o Initiate series of weekly vesigenurtacel-L dosing 
 
Monitor patients on site for potential acute reactions for 30 minutes after vesigenurtacel-L 
administration 
 
Record adverse events 
 
Send at least 4, non-stained, 10 micron sections from most recent staging procedure for evaluation 
of antigen expression.  If slides are not available, formalin-fixed paraffin embedded (FFPE) tissue 
(50 microns) is also acceptable. 
6.1.3.3 Phase 1 Assessments at Week 2 (Day 8) through Week 6 (Day 36) 
The following procedures will be performed at each of the weekly visits for Week 2 (Day 8 ±1), Week 3 
(Day 15±1), Week 4 (Day 22±1), Week 5 (Day 29±1), and Week 6 (Day 36±1): 
 
Study product administration  
o Weekly vesigenurtacel-L dosing 
 
Monitor patients on site for potential acute reactions for 30 minutes after vesigenurtacel-L 
administration  
 
Record adverse events 
 
Record concomitant medications 
6.1.3.4 Phase 1 Assessments at Week 7 (Day 43±1) 
The following procedures will be performed at this visit: 
 
Physical exam (symptoms, weight and vital signs only) 
 
12-lead ECG 
 
Blood draw for immune monitoring 
 
Hematology, serum chemistry, urinalysis 
 
Cystoscopy/Cytology and if indicated, a repeat biopsy – per SOC to evaluate for evidence of 
disease.  Note: Patients with evidence of disease may continue on treatment if judged by the 
investigator to be in the patient’s best interest.  Patients who discontinue study treatment will 
continue in long-term follow-up.  If biopsy was performed; provide at least 4, non-stained, 10 
micron sections for TCR sequencing and analysis of infiltrating T-cells. If slides are not available, 
FFPE tissue (50 microns) is also acceptable. 
 
Record adverse events 
 
Record concomitant medications 

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6.1.3.5 Phase 1 Assessments at Week 8 (Day 50) through Week 13 (Day 85) 
The following procedures will be performed at each of the weekly visits for Week 8 (Day 50 ±1), Week 9 
(Day 57 ±1), Week 10 (Day 64±1), Week 11 (Day 71±1), Week 12 (Day 78±1), and Week 13 (Day 85±1): 
 
Study product administration  
o Weekly vesigenurtacel-L dosing 
 
Monitor patient on site for potential acute reactions for 30 minutes after vesigenurtacel-L 
administration  
 
Record adverse events 
 
Record concomitant medications 
6.1.3.6 Phase 1 Assessments at Week 14 (Day 92 ±1) 
The following procedures will be performed at this visit: 
 Physical examination (symptoms, weight, vital signs only) 
 Blood draw for immune monitoring 
 12-lead ECG 
 Hematology, serum chemistry, urinalysis 
 Autoimmune Labs (ANA, TSH, ESR, and C-reactive protein; RF, T3, T4, and thyroid antibodies 
if clinically indicated) 
 Assessment of adult autoimmune system disorders (including: eye exam for dry eyes, lymph node 
and joints assessment for swelling, and skin exam for vitiligo and rash) 
 Record adverse events 
 Record concomitant medications 
6.1.3.7 Phase 1 Assessments at Week 17 (Day 113 ±3) 
The following procedures will be performed at this visit: 
 
Study product administration  
o Start series of monthly vesigenurtacel-L dosing 
 
Monitor patient on site for potential acute reactions for 30 minutes after vesigenurtacel-L 
administration  
 
Record adverse events 
 
Record concomitant medications 
6.1.3.8 Phase 1 Assessments at Week 21 (Day 141 ±3) 
The following procedures will be performed at this visit: 
 
Cystoscopy/Cytology and if indicated, a repeat biopsy – per SOC to evaluate for recurrent disease. 
Note: Patients with evidence of disease may continue on treatment if judged by the investigator to 
be in the patient’s best interest.  Patients who discontinue study treatment will continue in long-
term follow-up. If biopsy was performed; provide at least 4, non-stained, 10 micron sections for 

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TCR sequencing and analysis of infiltrating T-cells. If slides are not available, FFPE tissue (50 
microns) is also acceptable. 
 
Hematology, serum chemistry, urinalysis 
 
Study product administration  
o Monthly vesigenurtacel-L dosing 
 
Monitor patient on site for potential acute reactions for 30 minutes after vesigenurtacel-L 
administration  
 
Record adverse events 
 
Record concomitant medications 
6.1.3.9 Phase 1 Assessments at Week 25 (Day 169 ±3) 
The following procedures will be performed at this visit: 
 
Study product administration  
o Final monthly vesigenurtacel-L dosing 
 
Monitor patient on site for potential acute reactions for 30 minutes after vesigenurtacel-L 
administration  
 
Record adverse events 
 
Record concomitant medications 
6.1.3.10 Phase 1 Week 29 (Day 197 ±3) – End of Treatment Visit (4 weeks post last dose)  
The following procedures should be completed approximately four weeks following last dose of 
vesigenurtacel-L, including patients who discontinue vesigenurtacel-L dosing prematurely. 
 
Physical exam (full examination as well as weight and vital signs) 
 
12-lead ECG 
 
Blood draw for immune monitoring 
 
Hematology, serum chemistry, urinalysis 
 
Urine or serum pregnancy test for female patients of childbearing potential 
 
Autoimmune Labs (ANA, TSH, ESR, and C-reactive protein are required; RF, T3, T4, and 
thyroid antibodies if clinically indicated) 
 
Assessment of adult autoimmune system disorders (including: eye exam for dry eyes, lymph node 
and joint assessment for swelling, and skin exam for vitiligo and rash) 
 
Record concomitant medications 
 
Record adverse events 
6.2 
Phase 2 
 

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6.2.1 
Phase 2 Schedule of Events 
1 Screening evaluations should be completed ≤ 2 weeks of first dose.   
2 PE, hematology, chemistry, LDH, dipstick urinalysis and pregnancy test do not need to be repeated at Baseline if they were performed at Screening within three days prior to first 
dose. 
3 First dose of study product should occur within 6 weeks of baseline staging procedure. 
4 Weekly study evaluations should be completed within ±1 day of the target visit date.  
5 EOT evaluations should be completed 4 weeks ±3 days after last dose of study product or early discontinuation of study treatment. 
Procedure 
Screen Baseline Week 
13 
Weeks 
2-64 
Week 
7 
Weeks 
8-124 
Week 
13 
Weeks 
14-164 
Week  
25 
Weeks 
26-2716 
Week 
28 
Week 
37 
Week 
49 
Weeks 
50-5216 
Week 56 
(EOT)5 
Long-term 
Follow-up 
Study Day 
≤ -4 
wks. 
-3 to 1 
1 
 
43 (±1)  
85 (±1)  
169 
(±3) 
 
190 
(±3) 
253 
(±3) 
337 
(±3)  
386 (±3) Q3mos. 2yrs; 
Q6mos. 3rd yr 
Baseline Documentation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verify All Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment/Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam6 
X 
X2 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Pathology Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory Studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunologic Response7 
 
X 
 
 
X14 
 
X 
 
 
 
X14 
 
 
 
X 
 
Hematology, Chemistry and LDH, 
Dipstick Urinalysis 
X1 
X2 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
Pregnancy Test (urine or serum) 
X1 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Autoimmune Labs8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Tumor Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cystoscopy/Cytology 
for 
disease 
recurrence per SOC9 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
 
X15  
Tumor collection for antigen screen  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Product Administration10 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
 
BCG Administration11 
 
 
X 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
Other Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoimmune Phenomena12 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Adverse Events13 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X1 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival and subsequent therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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6 PE at screening and Week 56 (End of Treatment) will have a full examination of body systems and vital signs. Other PE evaluations will be limited to symptoms, weight and vital 
signs. 
7 70mL of heparinized blood, 10mL of non-heparinized blood, and 24mL urine will be collected at the indicated visits. 
8 ANA, TSH, ESR, C-reactive protein are required. Other tests (e.g. RF, T3, T4, thyroid antibodies) will be performed only as clinically indicated. 
9 All patients will have a cystoscopy/cytology performed at Week 13. If clinically indicated, a repeat biopsy will be performed. Patients with evidence of disease at an assessment 
may continue on treatment if judged by the investigator to be in the patient’s best interest (e.g. would normally receive another course of BCG therapy as SOC).  Upon 
discontinuation of study treatment, additional treatment will be at the discretion of the treating physician, and patients will continue in long-term follow-up on the study.  
10 For Arms 1-4: Patients will receive study product as the number of intradermal injections required to reach the number of cells per dose with no more than 0.1 mL per injection 
(approximately 4-6 injections). Patients should remain on site for 30 minutes following each vaccination for observation of adverse events. 
11 For Arms 1-3 only. 
12 Includes eye exam for dry eyes, lymph node and joint assessment and skin exam for vitiligo and rashes. 
13 AEs should be recorded from first dose through four weeks following the last dose of study medication regardless of the causal relationship to the study medication.  AEs considered 
related to study medication should be recorded at any time regardless of when they occurred.  
14 Samples to be collected prior to dosing 
15 Cystoscopy/Cytology for disease recurrence per SOC (approximately every 3 months for 2 years then every 6 months for up to a year).  Patients who are determined to have 
evidence of disease will have SOC treatment per the discretion of the investigator and will continue in long-term follow-up on the study. 
16 Weekly study evaluations should be completed within ±3 days of the target visit date. 
 

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6.2.2 
Phase 2 Screening Procedures 
The following procedures must be conducted ≤4 weeks prior to the first dose of study product: 
 
Written informed consent 
 
Verify eligibility criteria 
 
Patient demographics 
 
Pathology Review 
o Verification of Bladder Cancer Staging at the time of the baseline staging procedure (refer 
to Appendix 1) High-risk or intermediate-risk non-muscle invasive disease must be 
histologically/cytologically confirmed.  There will be no central pathology review.  In the 
event that multiple diagnostic procedures are performed for this occurrence of disease, 
dates of all procedures will be captured. 
o Verification of cancer sub-type (transitional cell carcinoma, squamous cell carcinoma, 
adenocarcinoma or undifferentiated carcinoma) 
o Verification of the date of baseline staging procedure (must be within 6 weeks) 
 
Physical examination (including weight, vital signs [heart rate, temperature, respiratory rate and 
blood pressure]) 
 
12-lead electrocardiogram (ECG) 
The following procedures must be conducted ≤2 weeks prior to the first dose of study product: 
 
Medical history, including concomitant medications within 14 days of first dose 
 
Hematology, chemistry with LDH, and dipstick urinalysis 
 
Urine or serum pregnancy test for female patients of childbearing potential  
6.2.3 
Phase 2 On-Study Procedures 
Study-related procedures and assessments performed during treatment on study are detailed as follows and 
in the Schedule of Events table (see Section 6.2.1).   
6.2.3.1 Phase 2 Baseline Assessments (Day -3 to Day 1) 
The following activities may be performed within three days of enrollment/randomization or on Day 1 prior 
to enrollment/randomization: 
 
Update of medical history including concomitant medications 
 
Blood and urine collection for immune monitoring 
 
Physical examination (symptoms, weight, vital signs only if screening exam performed more than 
three days prior to first dose) 
 
Hematology, chemistry with LDH, and dipstick urinalysis (unless screening labs obtained within 
three days of first dose) 
 
Urine or serum pregnancy test for female patients of childbearing potential (unless screening labs 
obtained within three days of first dose) 

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 
Autoimmune Labs (ANA, TSH, ESR, and C-reactive protein are required; RF, T3, T4, and thyroid 
antibodies if clinically indicated) 
 
Autoimmune Phenomena – Assessment of adult autoimmune system disorders (including: eye 
exam for dry eyes, lymph node and joint assessment for swelling, and skin exam for vitiligo and 
rash) 
Once the patient has met all of the eligibility requirements for the study, patients who will receive BCG 
will be randomized (treatment assigned within IWRS).  Each patient will be considered enrolled in the 
study at the time of first dose. 
6.2.3.2 Phase 2 Assessments at Week 1 (Day 1) 
The following procedures will be performed after all the previous baseline procedures have been completed: 
 
Study product administration  
o Initiate series of weekly study product dosing (dosing should begin within 6 weeks of 
baseline staging procedure) 
o Initiate series of weekly BCG dosing (Arms 1-3 only) 
o Monitor patient on site for potential acute reactions for 30 minutes after study product 
administration  
 
Record adverse events 
 
Record concomitant medications 
 
Send at least 4, non-stained, 10 micron sections from baseline staging procedure for evaluation of 
antigen expression.  If slides are not available, formalin-fixed, paraffin-embedded (FFPE) tissue 
(50 microns) is also acceptable. 
6.2.3.3 Phase 2 Assessments at Week 2 (Day 8) through Week 6 (Day 36) 
The following procedures will be performed at each of the weekly visits for Week 2 (Day 8 ±1), Week 3 
(Day 15±1), Week 4 (Day 22±1), Week 5 (Day 29±1), and Week 6 (Day 36±1): 
 
Study product administration  
o Weekly study product dosing 
o Weekly BCG dosing (Arms 1-3 only) 
o Monitor patient on site for potential acute reactions for 30 minutes after study product 
administration  
 
Record adverse events 
 
Record concomitant medications 
6.2.3.4 Phase 2 Assessments at Week 7 (Day 43±1) 
The following procedures will be performed at this visit: 
 
Blood and urine collection for immune monitoring collected prior to dosing 
 
Study product administration  
o Weekly study product dosing 

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o Monitor patient on site for potential acute reactions for 30 minutes after study product 
administration  
 
Record adverse events 
 
Record concomitant medications 
6.2.3.5 Phase 2 Assessments at Week 8 (Day 50) through Week 12 (Day 78) 
The following procedures will be performed at each of the weekly visits for Week 8 (Day 50 ±1), Week 9 
(Day 57 ±1), Week 10 (Day 64±1), Week 11 (Day 71±1), and Week 12 (Day 78±1): 
 
Study product administration  
o Weekly study product dosing 
o Monitor patient on site for potential acute reactions for 30 minutes after study product 
administration  
 
Record adverse events 
 
Record concomitant medications 
6.2.3.6 Phase 2 Assessments at Week 13 (Day 85±1) 
The following procedures will be performed at this visit: 
 
Physical exam (symptoms, weight and vital signs only) 
 
Blood and urine collection for immune monitoring 
 
Hematology, chemistry with LDH, and dipstick urinalysis 
 
Cystoscopy/Cytology and, if indicated, a repeat biopsy – per SOC to evaluate for evidence of 
disease.  Note: Patients with evidence of disease may continue on treatment if judged by the 
investigator to be in the patient’s best interest.  Patients who discontinue study treatment will 
continue in long-term follow-up.  If biopsy was performed, provide at least 4, non-stained, 10 
micron sections for TCR sequencing and analysis of infiltrating T-cells. If slides are not available, 
FFPE tissue (50 microns) is also acceptable. 
 
Autoimmune Phenomena – Assessment of adult autoimmune system disorders (including: eye 
exam for dry eyes, lymph node and joints assessment for swelling, and skin exam for vitiligo and 
rash) 
 
Record adverse events 
 
Record concomitant medications 
6.2.3.7 Phase 2 Assessments at Week 14 (Day 92) through Week 16 (Day 106) 
The following procedures will be performed at each of the weekly visits for Week 14 (Day 92 ±1), Week 
15 (Day 99 ±1), and Week 16 (Day 106 ±1): 
 Study product administration  
o Weekly study product dosing 
o Weekly BCG dosing (Arms 1-3 only) 
o Monitor patient on site for potential acute reactions for 30 minutes after study product 
administration  

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 Record adverse events 
 Record concomitant medications 
6.2.3.8 Phase 2 Assessments at Week 25 (Day 169) 
The following procedures will be performed at the visit for Week 25 (Day169±3): 
 
Hematology, chemistry with LDH, and dipstick urinalysis 
 
Cystoscopy/Cytology and, if indicated, a repeat biopsy – per SOC to evaluate for recurrent 
disease. Note: Patients with evidence of disease may continue on treatment if judged by the 
investigator to be in the patient’s best interest.  Patients who discontinue study treatment will 
continue in long-term follow-up.  If biopsy was performed, provide at least 4, non-stained, 10 
micron sections for TCR sequencing and analysis of infiltrating T-cells. If slides are not 
available, FFPE tissue (50 microns) is also acceptable. 
 
Record adverse events 
 
Record concomitant medications 
6.2.3.9 Phase 2 Assessments at Week 26 (Day 176) and Week 27 (Day 183) 
The following procedures will be performed at each of the weekly visits for Week 26 (Day 176±3) and 
Week 27 (Day 183±3): 
 
Study product administration  
o Weekly study product dosing 
o Weekly BCG dosing (Arms 1-3 only) 
o Monitor patient on site for potential acute reactions for 30 minutes after study product 
administration  
 
Record adverse events 
 
Record concomitant medications 
6.2.3.10 Phase 2 Assessments at Week 28 (Day 190±3) 
The following procedures will be performed at this visit: 
 Blood and urine collection for immune monitoring collected prior to dosing 
 Study product administration  
o Weekly study product dosing 
o Weekly BCG dosing (Arms 1-3 only) 
o Monitor patient on site for potential acute reactions for 30 minutes after study product 
administration  
 Record adverse events 
 Record concomitant medications 

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6.2.3.11 Phase 2 Assessments at Week 37 (Day 253) 
The following procedures will be performed at the visit for Week 37 (Day 253±3): 
 
Hematology, chemistry with LDH, and dipstick urinalysis 
 
Cystoscopy/Cytology and, if indicated, a repeat biopsy – per SOC to evaluate for recurrent 
disease. Note: Patients with evidence of disease may continue on treatment if judged by the 
investigator to be in the patient’s best interest.  Patients who discontinue study treatment will 
continue in long-term follow-up.  If biopsy was performed, provide at least 4, non-stained, 10 
micron sections for TCR sequencing and analysis of infiltrating T-cells. If slides or curls or fresh 
frozen specimens are not available, FFPE tissue (50 microns) is also acceptable. 
 
Record adverse events 
 
Record concomitant medications 
6.2.3.12 Phase 2 Assessments at Week 49 (Day 337) 
The following procedures will be performed at the visit for Week 49 (Day 337±3): 
 
Hematology, chemistry with LDH, and dipstick urinalysis 
 
Cystoscopy/Cytology and, if indicated, a repeat biopsy – per SOC to evaluate for recurrent 
disease. Note: Patients with evidence of disease may continue on treatment if judged by the 
investigator to be in the patient’s best interest. Patients who discontinue study treatment will 
continue in long-term follow-up.  If biopsy was performed, provide at least 4, non-stained, 10 
micron sections for TCR sequencing and analysis of infiltrating T-cells. If slides or curls or fresh 
frozen specimens are not available, FFPE tissue (50 microns) is also acceptable. 
 
Record adverse events 
 
Record concomitant medications 
6.2.3.13 Phase 2 Assessments at Week 50 (Day 344) through Week 52 (Day 358) 
The following procedures will be performed at each of the weekly visits for Week 50 (Day 344±3), Week 
51 (Day 351±3), and Week 52 (Day 358±3): 
 
Study product administration  
o Weekly study product dosing 
o Weekly BCG dosing (Arms 1-3 only) 
o Monitor patient on site for potential acute reactions for 30 minutes after study product 
administration  
 
Record adverse events 
 
Record concomitant medications 
6.2.3.14 Phase 2 Week 56 (Day 386 ±3) – End of Treatment Visit (4 weeks post last dose)  
The following procedures should be completed approximately four weeks following last dose of study 
product including patients who discontinue study product dosing prematurely. 
 
Physical exam (full examination as well as weight and vital signs) 
 
12-lead ECG 

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 
Blood and urine collection for immune monitoring 
 
Hematology, chemistry with LDH, and dipstick urinalysis 
 
Urine or serum pregnancy test for female patients of childbearing potential 
 
Autoimmune Labs (ANA, TSH, ESR, and C-reactive protein are required; RF, T3, T4, and 
thyroid antibodies if clinically indicated) 
 
Autoimmune Phenomena – Assessment of adult autoimmune system disorders (including: eye 
exam for dry eyes, lymph node and joint assessment for swelling, and skin exam for vitiligo and 
rash) 
 
Record concomitant medications 
 
Record adverse events 
6.3 
Long-term Follow-up Visits  
All patients will be followed for the procedures listed below every 3 months from the date of the previous 
visit for 2 years then every 6 months from the date of the previous visit for a year or until study termination, 
whichever occurs first: 
 
Survival 
 
New anticancer treatments initiated after disease recurrence 
 
TURBT or fulguration procedures 
 
Cystectomy 
In addition patients who have completed all study treatments or have discontinued study product dosing 
due to reason other than disease recurrence/progression will have the following procedures performed at 
each long-term follow-up visit: 
 
Cystoscopy/Cytology; biopsy if area suspicious for disease recurrence is identified at discretion of 
investigator (Note: patients who have a biopsy performed will provide at least 4, non-stained, 10 
micron sections for TCR sequencing and analysis of infiltrating T-cells.) If slides are not available, 
FFPE tissue (50 microns) is also acceptable.  
If a patient has recurrent/progressive disease and discontinues study treatment, the above disease 
assessment procedures will be discontinued, and subsequent long-term follow-up visits may be conducted 
via phone visit. 
6.4 
Blinding and Minimization of Bias 
The Phase 1 portion of the trial will be open label.  Ten patients will be enrolled in a single cohort that will 
receive low dose vesigenurtacel-L vaccine (1 x 106 cells) monotherapy.  If well-tolerated, the low dose as 
well as a higher dose (1 x 107 cells) will be advanced to Phase 2.  
The Phase 2 portion of the trial will have three blinded (physician-patient), placebo-controlled arms and 
one open label arm.  The placebo has been formulated with an intralipid suspension to visually resemble 
the vesigenurtacel-L vaccine.  Seventy-five patients who will receive BCG will be randomized to low dose 
vesigenurtacel-L in combination with BCG, high dose vesigenurtacel-L in combination with BCG, or 

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placebo in combination with BCG; 25 patients who will not receive BCG will be enrolled in an arm that 
will receive high dose vesigenurtacel-L vaccine monotherapy. 
Blinding in Phase 2 was indicated in order to be able to better facilitate ongoing evaluation of safety. 
7.0 
SUBJECT COMPLETION AND WITHDRAWAL 
7.1 
Subject Completion 
Patients may continue to receive study treatment until they complete the dosing phase of the study or meet 
the criteria for treatment discontinuation described in Section 7.2.1.  
7.2 
Subject Withdrawal from Study 
In accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) 
Guidelines, a patient has the right to withdraw from the study at any time for any reason without prejudice 
to his/her future medical care by the physician or at the institution.  The investigator and sponsor also have 
the right to withdraw patients from the study treatment, as described below or for safety, behavioral, or 
administrative reasons.  
7.2.1 
Discontinuation from Study Treatment 
Every effort must be made by study personnel to keep patients on study treatment.  However, a patient will 
be discontinued prior to completion of the study treatment for any of the following reasons: 
 
Grade 4 adverse event related to study product (or Grade 3 adverse event at the Principal 
Investigator’s discretion).  
 
Suspected Unexpected Adverse Drug Reaction, which requires patient unblinding 
 
Grade 3 or greater allergic reaction or autoimmune reaction 
 
Progressive disease 
 
Pregnancy 
 
Termination of the study by Heat Biologics 
 
Concurrent illness that prevents further administration of treatment  
Patients may also be discontinued prior to completion of the study treatment for any of the following 
reasons: 
 
Recurrent disease (Patients with recurrent disease at an assessment may continue on treatment if 
judged by the investigator to be in the patient’s best interest.) 
 
Significant deviation from protocol on the part of the patient (includes lack of compliance) 
 
Significant protocol violation on the part of the investigator 
 
The explanation of why the patient is discontinuing study treatment should be documented in the ECRF.  If 
the patient discontinues study treatment due to toxicity, “Adverse Event” will be recorded as the primary 
reason for withdrawal.  If a patient is prematurely discontinued from the study at any time due to an AE or 

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SAE, the patient must be followed until resolution to Grade 2 or less, unless it is unlikely to improve because 
of underlying disease. 
7.2.2 
Discontinuation from Study Follow-Up 
If a patient prematurely discontinues study treatment for any reason, the patient will continue to be followed 
for study endpoints, unless consent for this is specifically withdrawn.  If the patient withdraws consent for 
continued follow up, the investigator must make every effort to perform the EOT assessments four weeks 
following the last dose of study product, even if the patient has initiated other anticancer treatment. 
7.2.3 
Lost to Follow-Up 
If a patient fails to return for the necessary visits or discontinues prematurely from treatment, a genuine 
effort should be made to determine the reason why.  For a patient lost to follow-up there should be at least 
two documented attempts to contact the patient. 
7.2.4 
Replacement of Subjects 
Patients will not be replaced.  A 10% overage of patients has been included in the sample size to allow for 
patients who discontinue for reasons other than evidence of disease or toxicity or who are missing data. 
8.0 
INVESTIGATIONAL PRODUCT 
All production, formulation, and packaging of the investigational agent will be in accordance with 
applicable current Good Manufacturing Practice (cGMP) and meet applicable criteria for use in humans.  
8.1 
Description of Investigational Product, Vesigenurtacel-L 
Vesigenurtacel-L is a cell line derived from a human cancer cell line, designated as PC3.  The cell line was 
transfected with the plasmid cDNA ‘B45-neo-gp96Ig-HLA A1’. Vesigenurtacel-L has been irradiated to 
render cells replication incompetent while maintaining biological activity; i.e., expression of certain 
proteins. 
Manufacturing of vesigenurtacel-L includes expansion of batches of cells with testing for presence of 
expression of HLA-A1 by fluorescence-activated cell sorter and gp96-Ig by enzyme-linked immunosorbent 
assay (ELISA).  Cells are harvested, washed, resuspended in buffer, and irradiated at 12,000 rad. 
The vesigenurtacel-L vaccine to be injected will contain irradiated cells expressing HLA-A1 on at least 
70% of the cells and produce ≥60ng gp96-Ig/24h x 1 million cells; the cells will have ≥70% viability by 
trypan blue exclusion. 
Vesigenurtacel-L is provided as frozen, single-dose vials either 1) as concentrated frozen liquid, which will 
require dilution by the pharmacist with sterile saline, or 2) as fully-diluted frozen liquid not requiring 
additional dilution.  In either case the final drug product will consist of cells resuspended in buffered saline 
containing human serum albumin (HSA), dimethyl sulfoxide (DMSO), and pentastarch and will be 
delivered at doses of either 1 x 106 cells or 1 x 107 cells. Overfill is factored into each vial to allow extraction 
of the full dose for patient administration.  Refer to the Pharmacy Manual for instructions for preparation 
and labeling. 

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8.2 
Description of Placebo 
A challenge for cell-based immunotherapy is the development of a placebo control that is safe for use in 
patients and which mimics the appearance and biophysical properties of intact cells in solution.  Toward 
this end, we will utilize a diluted suspension of Intralipid (Baxter), which is FDA approved for use in 
humans.  This Intralipid solution will be diluted to a final concentration of 0.15% in a buffered saline 
solution also containing HSA, DMSO, and pentastarch, but lacking vesigenurtacel-L cells. This solution 
closely resembles the appearance and viscosity of the vesigenurtacel-L vials used in the experimental arms 
of the study. 
Intralipid solution is contraindicated in patients with a soy, egg, or peanut allergy. 
8.3 
Dosage and Administration of Vesigenurtacel-L and Placebo 
At each dosing visit for Phase 2, the site must contact the IWRS for assignment of the dose vial.  Study 
product will be administered intradermally.  Each dose will be divided into the number of injections 
required to reach the number of cells per dose with no more than 0.1 mL per injection (approximately 4-6 
injections), and administered as spatially divided intradermal injections separated by approximately 4-5 cm 
in the same extremity to increase volume distribution and enhance antigen presentation to lymph node 
regions shared with the urinary bladder.  Dosing will rotate injection site extremities every four timepoints: 
antero-lateral left thigh, antero-lateral right thigh, left buttock, and right buttock.  Injection sites will be 
recorded and retained in the patient records.  If injection site reactions are reported as an AE, an alternative 
injection site may be used upon discussion with the sponsor.  
Missed doses may be made up depending on the timing of the dosing, after discussion with the sponsor.   
8.4 
Dosage and Administration of BCG (Phase 2) 
A full dose of BCG according to the investigator’s standard practice should be administered intravesically, 
unless dose reductions are deemed appropriate by the investigator to manage toxicity.  The induction phase 
consists of 6 weekly doses, and the maintenance phase includes three once-weekly doses at 3, 6, and 12 
months since the start of induction BCG.  Patients who receive 5 of 6 induction doses may continue to 
receive study product and maintenance BCG. 
Additional information can be found in the package inserts: 
(http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProdu
cts/UCM310364.pdf and http://www.merck.com/product/usa/pi_circulars/t/tice_bcg/ticebcg_pi.pdf).  
Dose reductions will follow those as defined in Section 8.5.2. 
8.5 
Treatment Assignment 
The definitions of the randomized arms relative to the intended intervention to be used in those arms will 
be as follows: 
Phase 1:  Vesigenurtacel-L Low Dose: 1 x106 cells per dose 
Phase 2: 
 
Arm 1: Vesigenurtacel-L consisting of 1 x 106 cells per dose + BCG 

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 
Arm 2: Vesigenurtacel-L consisting of 1 x 107 cells per dose + BCG 
 
Arm 3: Placebo (containing intralipid for blinding, but no cells) + BCG 
 
Arm 4: Vesigenurtacel-L consisting of 1 x 107 cells per dose 
 
In Phase 2, patients who will receive BCG will be randomized centrally to Arm 1, 2, or 3 using a stratified 
block design according to risk of recurrence (strata: high vs. intermediate risk) and CIS (strata: yes vs. no).  
Patients who will not receive BCG will be enrolled in Arm 4. 
 
Due to delays in the batch release of certain doses of vaccine, the randomization schedule may be 
temporarily revised from a 1:1:1 randomization to a 1:1 randomization, with one arm being briefly 
suspended.  During the period of revised randomization, each patient will maintain at least a 50% chance 
of receiving vaccine versus placebo.  Randomization strata will remain unchanged.  Upon batch release of 
the vaccine the randomization will return to the original 1:1:1 ratio.  In order to maintain the study blinding, 
temporary closure of certain arms will not be disclosed outside of the DMC except as needed for Informed 
Consent documents. 
 
8.5.1 
Schedule and Duration of Treatment 
The dose administration will follow the regimen outlined in Figure 2 below.   
Figure 2. Dosing Schedule 
 
In Phase 1, each patient will receive intradermal injections of vesigenurtacel-L weekly for 12 doses (doses 
administered on Weeks 1-6 with a vaccine holiday on Week 7 to allow for disease assessment, followed 
by Weeks 8-13), then monthly for 3 doses for up to a total of 15 doses, unless the criteria for treatment 
discontinuation are met.  Vesigenurtacel-L should be administered within the allowable windows of the 

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scheduled dose.  In Phase 2, each patient in Arms 1-3 will receive weekly intradermal injections of 
blinded study product in combination with intravesical induction BCG for 6 weeks followed by 6 weeks 
of blinded study product monotherapy with a vaccine holiday on Week 13 to allow for disease 
assessment, followed by three courses of three once-weekly injections in combination with intravesical 
maintenance BCG for a total of 21 doses, unless the criteria for treatment discontinuation are met.  
Patients in Arm 4 will receive weekly intradermal injections of vesigenurtacel-L for 12 doses, followed 
by three courses of three once-weekly injections for a total of 21 doses, unless the criteria for treatment 
discontinuation are met. 
8.5.2 
Dose Modifications 
Dose modifications of vesigenurtacel-L will not be permitted during the trial.   
BCG should be given at full strength with dose reductions as needed for management of toxicity according 
to the investigator’s standard of care.   
8.6 
Study Product Handling and Accountability 
8.6.1 
Preparation 
Vesigenurtacel-L and placebo must be thawed and labeled prior to injection.  In addition, certain batches 
will require dilution with sterile saline.  Preparation of the product and labeling procedures will be described 
in the Pharmacy Manual. 
8.6.2 
Labeling 
Study product will be labeled with the product name/placebo, the vial number, storage conditions, and other 
local regulatory requirements. 
8.6.3 
Storage 
Vesigenurtacel-L and placebo must be stored at ≤ -120C in the vapor phase of a liquid nitrogen dewar.  If 
liquid nitrogen storage is not available at the investigative site, a unit will be supplied by the study sponsor.  
The sponsor will also arrange for replacement of the liquid nitrogen at regular intervals to ensure that the 
proper storage temperature is maintained throughout the study. 
8.6.4 
Product Accountability 
The investigator or designee (where applicable) will be responsible for study product accountability, 
reconciliation, and record maintenance.  In accordance with all applicable regulatory requirements, the 
investigator or designated site staff (e.g., investigational drug pharmacist) must maintain current 
investigational product accountability records throughout the course of the study.  These records will 
contain the following information: 
 
Patient Study ID number 
 
Date, quantity, and vial number of agent received, dispensed, administered, lost, and destroyed  
 
Documentation of storage conditions 
These inventories must be made available for inspection by the study monitor.  The investigator will be 
responsible for ensuring that all used and unused trial supplies are accounted for.  At the end of the trial the 

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study monitor will also collect the investigational agent dispensing record.  A copy of the dispensing record 
should be kept at the site and maintained with the study records.  
8.7 
Treatment of Investigational Product Overdose 
As this is the first patient trial with vesigenurtacel-L, there have been no cases of overdose.  Treatment of 
any suspected or confirmed overdose with vesigenurtacel-L should be symptomatic, and supportive care is 
recommended in cases where overdose is suspected.  As described in the Investigator’s Brochure for 
vesigenurtacel-L, Heat Biologics does not recommend specific treatment for overdose or toxicity; however, 
the investigator should use appropriate clinical judgment in treating the overdose.  For the purposes of this 
study, an overdose of vesigenurtacel-L is defined as any dose 50% greater than the intended dose for that 
patient.  Appropriate supportive care measures would need to be provided to address these potential 
toxicities in the event of an overdose. 
8.8 
Occupational Safety 
Precautions should be taken to avoid direct contact with the investigational product.  A Material Safety 
Data Sheet (MSDS) describing occupational hazards and recommended handling precautions will be 
available to the investigator. 
9.0 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES 
9.1 
Permitted Medications and Non-Drug Therapies 
A single dose of mitomycin C or other standard intravesical treatment administered immediately post-
TURBT (for the current occurrence of non-muscle invasive bladder cancer) is permitted according to the 
investigative center’s standard practice. 
Maintenance BCG per the institution’s standard of care may be administered to patients in Phase 1 at any 
time.  Additional courses of maintenance BCG may be administered to patients in Phase 2 after the 
completion of study treatment per the protocol. 
All concomitant medications, including prescription and over-the-counter medications, taken during the 14 
days before the date of first dose, during the study treatment, and through 4 weeks post the last dose of 
study product will be documented.  Any concomitant medication(s), including herbal or vitamin 
preparations, taken during the study will be recorded in the ECRF.  At a minimum, the drug name, dose, 
and the dates of administration will be recorded.  Caffeine consumption will also be collected. 
Local and/or systemic injection reactions may be treated with anti-allergics, antipyretics, and/or analgesics 
in accordance with standard local practice and investigator’s clinical judgment. 
Pre-treatment of the vaccine injection site with anesthetic cream is allowed only after the Week 1 vaccine 
administration has been performed without it and injection pain has been documented as an AE. 
Repeat TURBT or fulguration procedures will be permitted only in the setting of persistent, recurrent, or 
progressive disease according to an investigator’s standard practice. 
9.2 
Prohibited Medications and Non-Drug Therapies 

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Prohibited concomitant medications include chronic use of systemic corticosteroids or other 
immunosuppressant medications.  Topical and inhalation steroids will be permitted.  No concomitant 
chemotherapy, immunotherapy (other than BCG according to the protocol schedule), immunosuppressive 
or other anti-cancer therapy will be permitted prior to progression/recurrence or study withdrawal for other 
reasons. 
Administration of other concomitant investigational agents for any indication, other than the 
vesigenurtacel-L vaccine, is not permitted in the treatment phase of this study and for 30 days prior to first 
dose. 
During long-term follow-up there are no prohibited medications, and patients may enroll in any 
investigational study for which they are eligible. 
9.3 
Supportive Care 
Patients should receive full supportive care during the study, including transfusions of blood and blood 
products, and treatment with antibiotics, antiemetics, antidiarrheals, and analgesics, and other care as 
deemed appropriate, and in accordance with their institutional guidelines.  Please see Section 9.2 for 
prohibited medications. 
10.0 ASSESSMENT OF EFFICACY 
10.1 Evaluation of Disease  
Monitoring for disease status via cystoscopy, cytology, and biopsy if indicated, will be conducted every 3 
months during treatment and follow up for 2 years then every 6 months for up to a year per SOC.  Disease-
free status is defined as no evidence of disease, which in turn is defined as negative cytology, negative 
cystoscopy, and negative biopsy if clinically indicated. 
Recurrence is defined as disease that has recurred to the same extent of disease (i.e. same stage/severity) or 
to a lower stage/severity of disease compared to screening.  
Persistent disease is defined as evidence of CIS disease by 6 months for patients with CIS at screening. 
Progression is defined as an increase in T stage from CIS or Ta (at screening) to T1 (lamina propria 
invasion), development of T2 or greater or lymph node (N+) disease or distant metastasis (M1), or an 
increase in grade from low to high per the IBCG recommendations. 
The stage of disease at the time of recurrence or progression will be captured to distinguish between 
recurrence to the same extent of disease as at screening (i.e. the same stage/severity) versus recurrence to a 
lower stage/severity of disease at screening versus persistent disease for CIS versus progression. 
The date of confirmation of recurrence or progression is defined as the earliest date on which the diagnosis 
had been made based on the findings of cystoscopy, urinary cytology, or some other diagnostic imaging 
technique regardless of whether the patient continues treatment.  For the purpose of clarity, in the situation 
where a patient with CIS documented at screening has evidence of CIS at the 3-month assessment, continues 
treatment, and still has evidence of CIS at 6 months, that patient will be assumed to have persistent disease 
from the date of randomization. 

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For intermediate-risk patients (i.e. without CIS) who have evidence of disease at the 3-month assessment, 
continue treatment, and still have evidence of disease at 6 months, the date of recurrence would be the date 
of the 3-month assessment. 
If requested, the cystoscopy and cytology reports and images may be appended to the ECRF with all patient 
identifier information removed and the study site and patient study number written on the report, which is 
to be signed and dated by the investigator. 
10.2 Immunologic Response 
Peripheral blood samples and urine specimens will be obtained at time points according to the Schedule of 
Events.  All samples will be shipped to and processed by one or more central laboratories. 
Seventy (70) mL heparinized blood and 10 mL of non-heparinized blood will be drawn at each time point 
and used for analysis as outlined below.  Peripheral blood mononuclear cells (PBMCs) will be isolated from 
heparinized blood samples by Ficoll separation.  Isolated PBMCs will be utilized for immunophenotyping 
analysis using flow cytometry, DNA isolation and subsequent T cell receptor sequencing, intracellular 
cytokine analysis, and ELISPOT assays as described below.  Serum will be collected from non-heparinized 
blood samples and stored for batch analysis of antibody titers and serum cytokines/chemokines. 
Twenty-four (24) mL of urine will be collected at each time point.  Part of each sample will be centrifuged 
and cell counts determined.  If there are sufficient numbers of cells, samples may be analyzed by multicolor 
flow cytometry using standard procedures to examine lymphocyte subsets.  The remainder of each sample 
will be frozen for batch analysis of inflammatory cytokines. 
In addition to the analyses specified below, subsequent exploratory mechanistic analyses, the nature of 
which will be determined by emerging PBMC and tumor biopsy data on the immunological environment 
pre- and post-vaccine, may also be performed. 
10.2.1 Production of Interferon-gamma from CD8+ T Cells (ICS Assay) 
The immune response will be evaluated by antigen-specific flow cytometry and/or ELISPOT analysis for 
IFNγ production by patient T cells.  These ICS assays will be done under Good Laboratory Practice (GLP)-
like conditions using standard operating procedures and validating assays with standardized negative and 
positive controls.  Processing of all patient samples by a single facility in large batches will be performed 
to minimize assay variability between samples. 
Thawed and isolated PBMCs will be challenged or restimulated with specific tumor vaccine antigens as 
follows: 
 
PBMCs alone (negative control) 
 
PBMCs + PMA + Ionomycin (positive control) 
 
PBMCs + vesigenurtacel-L whole cell lysates (vaccine) 
 
PBMC + a cocktail of known shared antigens, including survivin, LAGE-1s, MAGE-A1, and 
MAGE-A3 
A maximum of four stimulation conditions at each time point per blood sample will be set up.  

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For the flow cytometry assay, following in vitro stimulation, cells will be harvested and labeled with 
antibodies to cell surface markers, including CD4 and CD8, and then fixed, permeabilized, and stained for 
the indicated intracellular markers, including IFNγ and gzB.  Samples will be analyzed by flow cytometry 
immediately after staining. 
For the ELISPOT assay, the frozen PBMCs will be thawed, antigen challenged, plated for analysis of 
IFN and gzB production by ELISPOT assay, and analyzed in triplicate for each time point for each 
patient.  If cells are limiting, IFNγ analysis will be prioritized.  Following incubation, samples will be 
quantitated in an automated ELISPOT reader. 
The frequency of IFN producing CD8+ cells is thought to mirror the frequency of cytotoxic CD8+ cells. 
However, cytotoxicity is primarily mediated by perforin and granzymes following granule exocytosis.  In 
some instances IFNγ secretion and granule exocytosis are uncoupled.  Therefore, the direct measurement 
of gzB secretion by ICS may provide a more direct readout for antigen-specific granule exocytosis and 
cytotoxicity.  For clinical efficiency it may be important to detect both IFN secretion and gzB exocytosis.  
Antigen specificity of the ICS response will be evaluable by comparing responses generated using the 
various stimulator cell populations and specific shared bladder cancer antigens as indicated.  This will also 
enable separation of the ‘allo-antigen’ specific response with the potential parent cell line tumor-antigen-
specific response.  Positive responses will be defined as a greater than two-fold increase in the number of 
IFNγ positive CD8+ T cells compared to baseline.  
10.2.2 PBMC Counts 
Total PBMC counts will be obtained from each patient from two sources. First, blood hematology will be 
performed for each patient at Baseline and the treatment weeks indicated in the Schedule of Events at the 
clinical centers. Second, the peripheral blood phenotyping analysis (described below) will be performed 
quantitatively for each of the markers indicated, providing a secondary measure of PBMC subsets defined 
by expression of the individual markers indicated. 
Total PBMC counts may be utilized as a surrogate endpoint for the overall health of a patient’s immune 
system.  
10.2.3 Phenotyping of Blood Lymphocyte Subsets 
Following alkaline lysis of red blood cells using standard procedures, peripheral blood samples will be 
stained using antibodies specific for the following cell markers: CD3, CD4, CD8, CD19, CD25, CD45, 
CD56, and FoxP3.  Samples will be analyzed by multicolor flow cytometry using standard procedures.  
Flow cytometric analysis of patient peripheral blood samples will quantitatively determine the frequency 
and number of lymphocytes (CD45+), B cells (CD45+CD3-CD19+), helper T cells (CD45+CD3+CD4+), 
cytotoxic T cells (CD45+CD3+CD8+), regulatory T cells (CD3+CD4+CD25+FoxP3+), and natural killer 
cells (CD45+CD56+) at baseline and over the course of therapy.  In addition a T cell activation panel (CD4, 
CD8, Ki67, perforin, IFNγ) will be performed before and after in vitro stimulation with PMA/ionomycin, 
a regulatory T cell panel (CD4, CD25, FoxP3, CD127, CD45-RA), a myeloid suppressor cell panel (CD39, 
CD11b, CD124, CD45, HLA-DR, CXCR4), and T cell suppression panel (CD4, CD8, CTLA-4, PD-1, 
Tim-3) will be performed on freshly isolated PBMC. 

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10.2.4 TCR Sequencing 
ELISPOT and intracellular cytokine assays are frequently used to monitor patient immune response to 
immunotherapy, despite the knowledge that these assays have not previously been strongly predictive of 
clinical response.  Thus, prognostic immune monitoring assays are highly desired.  If T cell receptor (TCR) 
clones are present that recognize antigens introduced by vesigenurtacel-L, clonal expansion of these cells 
is indicative of effective vaccination and potentially predictive for the presence of patient-tumor antigen 
specific T cells. 
TCR genomic DNA extracted from tumor tissue and PBMCs will be amplified and sequenced. 
The Phase 2 study is designed to explore the feasibility of application of this approach to later phase studies.  
In addition, data generated using this approach during Phase 2 may later be compiled with a larger data set 
to investigate the prognostic significance of individual TCR sequences before and during treatment with 
vesigenurtacel-L. 
Although this assay is potentially predictive of a clinical response, it remains an exploratory endpoint in 
this trial because this analysis can only be confirmed once expansion of individual T cell clones is found to 
correlate (or not) with improved patient survival.  Thus, the TCR sequencing data will be analyzed both 
before the survival data has matured in order to ascertain whether there are conserved sequences expanded 
for patients with similar HLA types but also to determine whether a clonal TCR signature emerges that has 
the potential to be used as a predictive biomarker for response in subsequent trials. 
10.2.5 Analysis of Infiltrating T Cells (Post-Treatment Tumor Biopsy) 
If a biopsy is performed at any time post-treatment, the tissue will also be examined for presence of 
infiltrating T-cells (TILs).  Two-color fluorescence immunohistochemistry (IHC) and multicolor 
fluorescence-activated cell sorting analysis will be used for quantification of CD8+ T cells and 
measurement of their activation status (CD69-expression) and cytotoxic activity (CD107a-expression) in 
situ.  These data will be correlated with clinical response. 
10.2.6 Antigen Screening of Resected Tumor Tissue  
A sample containing at least 4, non-stained, 10 micron sections will be collected for the purpose of 
screening the tissue for representative antigen expression (LAGE-1, NY-ESO-1, MAGE-[A1-10], CT7, 
CT10, GAGE, etc.), expression of MHC class I, and expression of immunosuppressive molecules, 
including, for example, CTLA-4, PD-L1 and PD-1, by mRNA expression and/or IHC analysis.  If slides 
are not available, FFPE tissue (50 microns) is also acceptable. These data will be retrospectively correlated 
with immune response to determine if a particular antigen expression profile may predict response to 
treatment. 
The tumor arrays will be processed by IHC and PCR according to standard methods.  Bound antibodies 
will be visualized by using the avidin-biotin complex method according to the recommendations of the 
supplier (Vectastatin Elite ABC Kit; Vector Laboratories Inc., Burlingame, CA). Diaminobenzidine will be 
used as chromogen.  57B staining will be classified as follows: no staining; “weak,” indicating low-intensity 
staining regardless of positive cell percentages or medium intensity staining of no more than 20% of cells; 
“moderate,” indicating medium-intensity staining of more than 20% of cells or high-intensity staining of 
no more than 20% of cells; “strong,” indicating high-intensity staining of more than 20% of cells.  Only 

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moderately and strongly positive cases will be considered positive.  For PCR based analysis, total RNA 
will be isolated from collected tissue samples and reverse transcribed to cDNA using standard methods.  
The expression of tumor antigens from cDNA samples will then be interrogated using real-time PCR and a 
variety of specific tumor antigen probes. 
11.0 SAFETY ASSESSMENTS 
Safety will be assessed throughout the study by a qualified physician, physician assistant, or nursing staff.  
Measurements used to evaluate safety will include history, physical examination, vital signs, clinical 
laboratory tests, urinalysis, 12-lead ECG, and monitoring for AEs.  AEs will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (NCI-CTCAE 
v4.03) NCI, 2010. 
Laboratory measurements that deviate significantly (as determined by the investigator) from previous 
measurements may be repeated.  If warranted, additional or more frequent testing than is specified in the 
protocol should be done to provide adequate documentation of AEs and the resolution of AEs. 
11.1 Physical Examination 
Medical and physical examinations must be performed by a qualified physician, nurse practitioner, or 
physician assistant and should include a thorough review of all body systems at Screening, Baseline, and 
End of Treatment.  Examinations should be performed as listed on the schedule of events.  Physical 
examinations will include vital signs (heart rate, temperature, respiratory rate, and blood pressure).  Blood 
pressure, heart rate, and respiration rate will be measured after resting in a semi-supine or supine position, 
and patients must be in the same position at each assessment for at least 5 minutes before and during the 
assessment.  Physical examinations at Weeks 7 and 14 in Phase 1 and Week 13 in Phase 2 are limited to 
vital signs and symptoms. 
11.2 Clinical Laboratory Tests 
Patients will have blood samples collected for routine clinical laboratory testing.  The clinical laboratory 
parameters will be analyzed at the site’s local laboratory.  Laboratory assessments to be completed will 
include hematology, chemistry, and urine or serum pregnancy test (females of childbearing potential). 
Laboratory assessments will be defined as follows: 
 
Chemistry: To include sodium, calcium, total protein, albumin, creatinine, blood urea nitrogen, 
total bilirubin, alkaline phosphatase, AST, ALT, potassium, chloride, bicarbonate, lactate 
dehydrogenase, and glucose. 
 
Hematology: To include white blood cell (WBC) with differential, platelet count, hemoglobin, and 
red blood cell (RBC) count. 
 
Urine or serum preganancy test – See section 11.7 below for further details. 
 
Additional laboratory assessments may be conducted throughout the study as medically necessary. 

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11.3 Urinalysis 
Patients will have urine samples collected for routine urinalysis.  The urinalysis will include color, 
appearance, and dipstick for specific gravity, protein, white blood cell-esterase, glucose, ketones, 
urobilinogen, nitrite, WBC, RBC, and pH.  Microscopic analysis of urine will be performed if indicated 
based on macroscopic examination and urine dipstick results. 
11.4 ECG 
The following parameters from 12-lead electrocardiograms (ECG) will be evaluated: heart rate, PR interval, 
QRS duration, QT interval, and QTcF interval. 
11.5 Autoimmune Monitoring 
Autoimmune monitoring will occur through laboratory measurements of ANA, TSH, erythrocyte 
sedimentation rate (ESR), and C-reactive protein.  Other tests, such as rheumatoid factor (RF), T3, T4, and 
thyroid antibodies may be performed as clinically indicated.  Furthermore, periodic physical examinations, 
including eye exam for dry eyes, lymph node and joint assessment, and skin exam for vitiligo and rashes, 
will be performed. 
11.6 Injection Site Reactions 
The grading scale for injection site reactions (ISRs) used in this trial can be found in Appendix 3.  Grade 1 
ISRs consisting of mild redness, erythema, and swelling around the injection site are anticipated.  Grade 1 
reactions should dissipate over several days to a week with no special treatment.  All ISRs should be 
recorded on the Injection Site Reaction CRF page.  Attempts to obtain photographs at the peak of severity 
and at follow-up visits which show resolution over time are encouraged.  A ruler should be in the field of 
view to allow measurement of the size of the reaction.  If the patient consents, the de-identified 
photograph(s) should be appended to the ECRF. 
11.7 Pregnancy 
All female patients of childbearing potential will have a urine or serum pregnancy test performed at 
Screening, Baseline, and End of Treatment. 
Female patients who become pregnant during the study should discontinue study medication immediately.  
The patient will receive counseling from the investigator or designee regarding the nature of the study 
medication and the potential risk on fetal development. 
11.7.1 Time Period for Collecting Pregnancy Information 
The time period for collecting information on whether a pregnancy occurs is from the Screening visit to 
four weeks after the last dose of study medication.  Information on pregnancies identified prior to study 
product administration does not need to be reported to Heat Biologics. 
11.7.2 Action to Be Taken if Pregnancy Occurs 
The investigator will notify Heat Biologics, or designee, within one week of learning of a patient’s 
pregnancy.  The patient will also be followed to determine the outcome of the pregnancy.  Information on 

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the status of the mother and child will be forwarded to Heat Biologics, or designee.  Generally, follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date.  Any premature termination of 
the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE (see AE/SAE section of 
the protocol). 
A spontaneous abortion is always considered to be an SAE and will be reported as such.  Furthermore, any 
SAE occurring as a result of a post-study pregnancy and that is considered reasonably related to the 
investigational product by the investigator will be reported to Heat Biologics.  While the investigator is not 
obligated to actively seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting. 
11.7.3 Action to be Taken if Pregnancy Occurs in a Female Partner of a Male Study Subject 
The investigator will attempt to collect pregnancy information on any female partner of a male study patient 
who becomes pregnant while participating in this study.  The investigator will record pregnancy information 
on the appropriate form and submit it to Heat Biologics, or designee, within one week of learning of the 
partner’s pregnancy.  The partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to Heat Biologics, or designee.  
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date.  Any 
premature termination of the pregnancy will be reported. 
11.8 Adverse Events (AE) and Serious Adverse Events (SAE) 
The investigator is responsible for the detection and documentation of events meeting the criteria and 
definition of an AE or SAE, as provided in this protocol.  During the study when there is a safety evaluation, 
the investigator or site staff will be responsible for detecting, documenting, and reporting AEs and SAEs, 
as detailed in both this section of the protocol and in the AE/SAE section of the study procedures manual.  
AEs should only be recorded for up to four weeks following the last dose of study medication, unless the 
AE is considered related to the study medication, which requires that the AE be reported regardless of the 
amount of time that has passed since receiving the last dose of study medication. 
11.8.1 Definition of an AE 
An adverse event is any untoward medical occurrence associated with the use of a medicinal product in 
humans, whether or not considered related to the medicinal product (21 CFR 312.32 (a)).  Note: an AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease (new or exacerbated) temporally associated with the use of a medicinal product.  For marketed 
medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or 
misuse. 
A suspected adverse reaction (SAR) is defined as any AE for which there is reasonable possibility that the 
drug caused the AE (21 CFR 312.32 (a)). 
An AE or SAR is considered unexpected if it is not listed in the Investigator’s Brochure or is not listed at 
the specificity or severity that has been observed or, if an Investigator’s Brochure is not required or 

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available, is not consistent with the risk information described in the general investigational plan or 
elsewhere in the current application (21 CFR 312.32 (a)). 
11.8.2 Definition of an SAE 
The Code of Federal Regulations (CFR) Title 21 part 312.32 and ICH Guideline for Industry: Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting, ICH-E2a March 1995, as 
implemented by the US FDA, defines a SAE or serious adverse drug experience as any untoward medical 
occurrence at any dose that: 
 
Results in death (i.e., the AE actually causes or leads to death) 
 
Is life-threatening (with regards to determining if an AE is serious, “life-threatening” is defined as 
an AE for which the patient was at risk of death at the time of the event.  It does not refer to an 
event which hypothetically might have caused death if it were more severe.  If either the 
investigator or the sponsor believes that an AE meets the definition of life-threatening, it will be 
considered life-threatening) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
Results in a congenital anomaly/birth defect 
 
Results in any “other” important medical event.  Medical or scientific judgment should be exercised 
in deciding whether reporting is appropriate in other situations, such as important medical events 
that may not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition.  These should also be considered serious.  Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
11.8.3 Disease-Related Events or Outcomes Not Qualifying as SAEs 
An event that is part of the natural course of the disease under study (i.e., disease progression) should not 
be reported as an SAE.  Recurrence or progression of the patient’s neoplasia will be recorded in the clinical 
assessments in the ECRF.  Death due to disease progression is to be recorded on the Death ECRF page and 
not as a SAE.  However, if the progression of the underlying disease is greater than what would normally 
be expected for the patient, or if the investigator considers that there was a causal relationship between 
treatment with vesigenurtacel-L or protocol design/procedures and the disease progression, then it must be 
reported as an SAE.  Any new primary cancer must be reported as an SAE. 
11.8.4 Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs 
Abnormal laboratory findings (e.g., clinical chemistry, hematology, and urinalysis) or other abnormal 
assessments (e.g., ECGs or vital signs) that are judged by the investigator as clinically significant will be 
recorded as AEs and SAEs if they meet the definition of an AE or SAE.  Clinically significant abnormal 
laboratory findings or other abnormal assessments that are detected during the study or are present at 
baseline and significantly worsen following the start of the study will be reported as AEs or SAEs.  

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However, clinically significant abnormal laboratory findings or other abnormal assessments that are 
associated with the disease being studied, unless judged by the investigator as more severe than expected 
for the patient’s condition, or that are present or detected at the start of the study and do not worsen, will 
not be reported as AEs or SAEs. 
The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal 
laboratory finding or other abnormal assessment is clinically significant. 
11.8.5 Reporting Adverse Events 
The investigator will record all directly observed AEs and all AEs spontaneously reported by the study 
patient on the Adverse Event ECRF.  In addition, each study patient will be questioned about AEs. 
Each AE should be described in detail on the Adverse Event ECRF and SAEs on a Serious Adverse Event 
form and include the following information: start and stop dates, CTCAE v. 4.03 grading, relationship to 
study medication, action taken, and outcome.  AEs should be recorded from time of first dose up to four 
weeks following the last dose of study medication regardless of the causal relationship to the study 
medication.  AEs considered related to study medication should be recorded at any time regardless of when 
they occurred. 
The investigator will also assess the possible relationship between the AE and the study medication as well 
as any concomitant medications according to the following criteria: 
 
Related: AE and administration of study product are related in time, and a direct association can be 
demonstrated. 
 
Not related: AE is clearly explained by another cause not related to study product. 
Event outcome will be recorded using the following categories: 
 Recovered/resolved 
 Not recovered/not resolved 
 Recovered/resolved with sequelae 
 Fatal 
 Unknown 
11.8.6 Prompt Reporting of SAEs  
All SAEs, whether or not considered related to the investigational product, must be reported within 24 hours 
of becoming aware of the event to the Medical Monitor listed on the second page of this protocol.  The 
Medical Monitor will require the following patient information as listed on the SAE form: 
 
Subject identification, including patient study number, initials, and sex 
 
Date of first dose of investigational product 
 
Total dose and number of doses administered 
 
Date and amount of last dose of investigational product 

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 
Whether the patient was taking investigational product at the time of the AE 
 
Date, duration, and description of AE 
 
Events and/or symptoms leading up to the AE 
 
Action taken, including whether patient was withdrawn from study 
 
Concomitant therapy (including doses, routes, and regimens) 
 
Pertinent laboratory data 
 
Medical history (including time on study prior to AE and history that might be related to the AE) 
 
Dosing status of investigational product (e.g., interrupted, discontinued, dose changed) 
In addition to the above information, the Medical Monitor will require the investigator's assessment of the 
following: 
 
Intensity of the AE 
 
Investigator's assessment of the relationship of the AE to study treatment 
 
Outcome of the AE 
Any necessary follow-up must be submitted within a reasonable time thereafter.  The sponsor will promptly 
report SAEs to the FDA and other applicable regulatory agencies in accordance with Title 21 of the Code 
of Federal Regulations (CFR), Part 312.32 (21 CFR 312.32) and local regulatory requirements.  The 
investigator should also comply with any applicable requirements related to the reporting of SAEs to the 
IRB/IEC. 
The investigator will provide an SAE follow-up report to the sponsor.  In this report, the investigator is to 
assess and record the SAE in detail, including the date and time of onset, description, intensity, duration, 
outcome, etiology, relationship to study drug, and action taken.  Any SAEs that continue at the patient’s 
last study visit must be followed until the event resolves or follow-up is agreed to be adequate by the 
investigator, Medical Monitor, and sponsor. 
The clinical site investigator and the Medical Monitor will review each SAE report and evaluate the 
relationship of the SAE to study treatment and to underlying disease.  Based on the investigator’s and 
sponsor’s assessment of the SAE, a decision will be made concerning the need for further action.  The 
primary consideration governing further action is whether new findings affect the safety of patients 
participating in the clinical study.  If the discovery of a new SAE related to vesigenurtacel-L raises concern 
over the safety of continued administration of study drug to patients, the sponsor will take immediate steps 
to notify the FDA and all investigators participating in clinical studies of vesigenurtacel-L. 
Further action that may be required includes the following: 
 
Modification of the protocol 
 
Discontinuation or suspension of the study 

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 
Modification of the existing consent form and informing current study participants of new findings 
 
Addition of any newly identified vesigenurtacel-L-related AEs to the list of expected AEs 
12.0 STATISTICAL CONSIDERATIONS 
12.1 General Statistical Considerations 
Phase 1: 
Data from Phase 1 of the study will be presented descriptively.  Standard descriptive statistics will include 
the sample size, mean and standard deviation (SD), median, minimum, and maximum values for continuous 
variables.  For categorical variables, the frequency of patients will be provided along with the percentage 
based on the number of patients with available data.  Summaries will be based on observed data (i.e., no 
missing data will be imputed). 
Analysis of the secondary efficacy parameters will follow the same approach as outlined for Phase 2 below. 
Phase 2: 
In Phase 2, the primary endpoint (proportion of patients alive and disease free at one year) between the two 
experimental groups and the control will be compared using Fisher's exact test and presented as odds ratios 
(OR) with 95% confidence intervals (CI) relative to the control group.  For the statistical comparisons on 
the primary endpoint between the two experimental and control groups, there will be no adjustment for 
multiplicity.  ORs will be generated with a simple logistic regression model with one year disease-free 
survival as the dependent variable and group as the sole independent variable (low dose and high dose 
vesigenurtacel-L vs. control).  If the analysis of the primary endpoint does not suggest any dose response 
effect between the two vaccine arms, an exploratory analysis will be conducted where the two vaccine arms 
will be pooled and compared to the control arm for the primary endpoint (proportion of patients alive and 
disease-free at one year).  The outcome will be presented as OR with 95% CI relative to the control group. 
Efficacy comparisons between the monotherapy arm and any of the randomized arms will remain 
exploratory.  However, safety and point estimates with appropriate measures of variance (SD, 95% CI) for 
the efficacy parameters for the fourth arm will be estimated. 
The binary secondary endpoints will be presented as OR with appropriate 95% CI.  
DFS will also be evaluated as a time to event endpoint, defined as disease recurrence or progression or 
death from any cause.  For time to event endpoints, which will also include OS, time to cystectomy, and 
burden of repeat TURBT, survival curves will be generated by the method of Kaplan-Meier and compared 
with the log-rank test.  In an exploratory analysis, the weighted log rank test will also be used.  The weighted 
log rank preserves the statistical power that is lost due to the lag time effect in efficacy with 
immunotherapeutic agents. 
Exploratory clinical and laboratory endpoints will be summarized descriptively by time point of collection.  
Statistical testing and CI will be provided as an aid in reviewing the collected data.  A log10 transformation 
may be used as appropriate in order to determine 95% CI based on a t-test for the log-concentrations, and 
the bounds will be transformed back to the original scale for presentation purposes.  Homogeneity between 

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treatment groups will be assessed using Wilcoxon rank-sum tests for numeric variables and Fisher’s exact 
test for categorical variables. 
An unblinded Interim Analysis may be performed when all randomized patients have completed the disease 
assessment at Week 25. The primary goal of this analysis will be to allow selection of a dose and dosing 
regimen for future manufacturing efforts. At the time of this analysis all patients will have been enrolled, 
and the outcome of this analysis will not impact continuation of the trial to the primary endpoint. The 
treatment assignment of individual patients will not be unblinded to physicians or patients. 
All of the analyses will be performed using SAS® Version 9.1 (or later). Further details of the exact analysis 
methods can be found in the study-specific Statistical Analysis Plan. 
12.2 Analysis Populations 
Study populations are defined as follows 
Phase 1: 
Safety Population: defined as all patients receiving at least one dose of vesigenurtacel-L 
Phase 2: 
Intent-to-Treat (ITT): defined as all patients randomized into the study and who will be classified according 
to their assigned treatment group, regardless of the actual treatment received. 
Safety Population: defined as all randomized patients who receive at least one dose of treatment (BCG, HS-
410, or any combination thereof) 
Per-protocol population: defined as all patients in the ITT population who do not have any major protocol 
deviations (including being non-compliant to the study drug) 
Other sub-populations of patients for secondary and exploratory analyses may be defined at the time of 
statistical analysis and will be identified in any reporting of results. 
Patients will be randomized to Arms 1-3 centrally using a stratified block design according to risk of 
recurrence (strata: high vs. intermediate risk) and CIS (strata: yes vs. no).  The intent for stratification is to 
ensure balance between groups with respect to these important prognostic factors.  Given the limited sample 
size, a formal subgroup analysis based on the stratification variables will not be undertaken.  Patients who 
will not receive BCG will be consecutively allocated (non-randomized) into Arm 4 consisting of vaccine 
monotherapy. 
Due to delays in the batch release of certain doses of vaccine, the randomization schedule may be 
temporarily revised from a 1:1:1 randomization to a 1:1 randomization, with one arm being briefly 
suspended.  During the period of revised randomization, each patient will maintain at least a 50% chance 
of receiving vaccine versus placebo.  Randomization strata will remain unchanged.  Upon batch release of 
the vaccine the randomization will return to the original 1:1:1 ratio.  In order to maintain the study blinding, 
temporary closure of certain arms will not be disclosed outside of the DMC except as needed for Informed 
Consent documents. 

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12.3 Accountability, Demographics, and Baseline Characteristics 
Accountability information will be summarized for each phase, including the number of enrolled patients, 
dosed patients, and patients who terminated at the first disease assessment, and the number of patients 
withdrawn by reason.  Also, separately, the number of patients with recurrence events, dropping out, or 
continuing in the study will be summarized in order to show the percent of subjects without an event still 
being followed. 
Descriptive information on demographics and baseline data including age, sex, weight, height, body mass 
index, physical examination, and medical history will be provided in a summary table.  Summaries will be 
provided by treatment group and overall for the ITT and Per-Protocol population classifications. 
12.4 Safety Analysis  
Safety analysis will be performed for the Safety Population in each phase of the study. 
12.4.1 Adverse Events 
Treatment emergent adverse events (TEAEs) will be defined as events that occur on or after the first dose 
of study medication.  The Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary will 
be used for the coding of AEs.  TEAEs, serious or CTC Grade 3 or 4 TEAEs, and TEAEs related to therapy 
will be summarized overall and by system organ class and preferred term by treatment group.  These will 
summarize the number of events and the number and percent of patients with a given event.  A Fisher’s 
exact test will be provided to evaluate if the number of patients with an event within a specific system organ 
class is homogeneous across the treatment groups.  In addition, the number and percent of patients with 
TEAEs will be provided by maximum severity.  A summary of all TEAEs by system organ class and 
preferred term occurring in at least 5% of subjects in either treatment group will be provided by quarter. 
12.4.2 Laboratory Assessments 
All laboratory-based data will be presented as listings of all values as well as abnormal results judged to be 
clinically significant, which will also be reported as AEs.  Numeric summaries of all observed and change 
from baseline laboratory evaluations will be provided by visit and treatment group, including chemistry, 
hematology, and urinalysis results.  No inferential comparisons are planned. 
12.4.3 Vital Signs 
Numeric summaries of all observed and change from baseline vital signs will be provided by time point 
and treatment group, including blood pressure, heart rate, and temperature. No inferential analyses are 
planned for vital signs. 
12.4.4 ECGs and Physical Examination 
Physical examination data and changes will be presented as listings.  ECG results will be presented as 
listings and summarized by treatment group and visit based on incidence of clinically significant 
abnormalities.  No inferential comparisons across treatment groups are planned. 

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12.4.5 Other Assessments 
Other collected data not specifically mentioned, including physical examinations and protocol deviations, 
will be presented in subject listings. 
12.4.6 Safety of Vesigenurtacel-L (Phase 1 and Arm 4 of Phase 2 Only) 
Safety is defined as the number of adverse events (AE)/serious adverse events (SAE) in patients receiving 
vesigenurtacel-L. 
12.4.7 Safety of the Combination of Vesigenurtacel-L and BCG (Arms 1, 2, and 3 of Phase 2 Only) 
Safety is defined as the proportion of AE/SAE in patients receiving the combination of vesigenurtacel-L 
and BCG compared to the proportion of AE/SAE in patients receiving the combination of placebo and 
BCG. 
12.5 Efficacy Analysis (Phase 2) 
All efficacy analyses will be based on the ITT population unless otherwise specified. 
12.5.1 Primary Efficacy Analysis 
12.5.1.1 1-year Disease-Free Survival (1-yr DFS) 
One-year disease-free survival will be defined as the proportion of patients who are free from recurrent 
disease, progressive disease, and alive one year after the date of randomization/treatment assignment (Arm 
4).   
For the primary efficacy evaluation, disease-free survival at one year between the experimental groups and 
the control will be presented as the absolute difference in proportions, as well as the OR, with the associated 
95% CI. 
12.5.2 Analysis of Secondary Efficacy Parameters  
The Secondary Efficacy Parameters will be analyzed using Kaplan-Meier time-to-event methodology. 
12.5.2.1 Time to Recurrence 
Defined as the time from randomization to recurrence of disease to the same extent (stage and grade) as 
screening. 
12.5.2.2 Time to Progression 
Defined as the time from randomization to progression of disease to a greater stage. 
12.5.2.3 Disease-Free Survival 
Defined as time from randomization to recurrence or progression 
12.5.2.4 Overall disease-free survival 
Overall DFS is defined as the interval between the date of disease recurrence, progression, or death 
(whichever occurs first) and the date of randomization/treatment assignment (Arm 4) for patients without 
CIS.  For patients with CIS at screening who have persistent disease at 6 months, the date of disease 
persistence will be defined as the date of randomization/treatment assignment (Arm 4) (i.e. DFS = zero).  

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Patients with CIS at screening who are disease-free by 6 months will have their overall DFS interval 
calculated between the date of disease recurrence, progression, or death (whichever occurs first) and the 
earliest date that the patient was determined to be disease-free.  Patients will be censored at the last time of 
contact if recurrence, progression, or death has not been confirmed at the time of the analysis.  Overall DFS 
will be analyzed using a log-rank test with a term for treatment assignment.  In addition, Kaplan-Meier 
curves will be produced separately for each treatment group.  The weighted log rank test will also be applied 
in an exploratory manner. 
In a supporting analysis, a simple Cox proportional hazards model with treatment group as the sole 
independent variable will be built in order to estimate the hazard rate (HR) and 95%CI for overall DFS 
between the low and high dose vesigenurtacel-L groups relative to the control.  A HR of less than one will 
provide initial evidence of a favorable outcome with vesigenurtacel-L.  These analyses will be completed 
for the ITT and Per-Protocol populations. 
12.5.2.5 Overall survival 
OS is defined as the interval between the date of death and the date of randomization/treatment assignment 
(Arm 4).  Patients will be censored at the last time of contact if death has not been confirmed at the time of 
the analysis.  OS will be analyzed using a log-rank test with a term for treatment assignment.  In addition, 
Kaplan-Meier curves will be produced separately for each treatment group.  The analysis will be completed 
for the ITT and Per-Protocol populations. 
12.5.2.6 Burden of Repeat TURBT 
Defined as the proportion of patients with no repeat TURBT vs 1 TURBT vs 2 TURBT vs 3 TURBT etc 
within 12 months since randomization, within 18 months since randomization, and within 24 months since 
randomization. 
12.5.2.7 Time to Cystectomy 
Defined as the time from randomization to cystectomy. 
12.5.2.8 Immune Response 
Section 10.2.1 details how samples are run in duplicate or triplicate using ICS via flow cytometry or 
ELISPOT.  The first step in the analysis of immunologic response will be to form the subject average across 
the duplicate or triplicate measurements recorded at each time point.  In situations where only one 
measurement is obtained, the single value will be used in the analysis.  If any values are in the range (0,1) 
inclusive, a value of 0.5 will be used in the analysis of count information on the log10 scale. 
The observed and log10 transformed values will be summarized for each visit.  In addition, the change from 
baseline will also be summarized descriptively.  At each visit and for the last available visit, a sign-rank 
test will be used to evaluate the null hypothesis that the change from baseline is centered at zero separately 
for each of the dosing groups.  Similarly, a Wilcoxon rank-sum test will be used to evaluate the null 
hypothesis that the observed and change from baseline values have a similar location ((i.e. median) between 
the low and high dose groups.)  A 95% CI for the ratio of the differences geometric mean will be obtained 
by back-transforming the 95% non-parametric CI for the difference in log10 analysis.  For the purposes of 
identifying the most important comparison, the analysis of the last assessment will be considered the 
primary analysis with other time points considered secondary analyses.  Additionally, a repeated measures 
analysis will be completed modeling log10 transformed values as a function of visit, treatment, and a visit 

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by treatment interaction.  Model results may not be reported if convergence is unattainable because of the 
small sample size. 
These analyses will be completed using the ITT and Per-Protocol populations. 
12.5.2.9 Exploratory Efficacy Analyses 
In an exploratory analysis, patients experiencing an immune response in all four treatment arms will be 
compared to those who did not experience an immune response.  The analysis will include a univariate 
comparison of patient and clinical variables at baseline as well as a comparison of any difference between 
immune responders and non-responders for the following endpoints: proportion with progressive or 
recurrent disease at selected time points, disease-free survival, proportion undergoing post-treatment 
TURBT or fulguration or cystectomy, and overall survival. 
In an additional exploratory analysis, the proportion of patients whose disease has recurred to a lower 
stage than at screening and the proportion of patients whose disease has recurred to the same extent as at 
screening will be compared between the experimental and control groups and presented as an OR with 
95% CI. 
12.6 Sample Size Estimations 
12.6.1 Phase 1 
Phase 1 is designed to provide some indication of safety and tolerability of the low dose of vesigenurtacel-L 
as a monotherapy.  A sample size of 10 patients in the monotherapy setting is deemed suitable for an 
assessment of safety. 
12.6.2 Phase 2 
For the randomized portion, a sample size of 75 subjects in the ITT population was selected for this study. 
The sample size assessment was based on the following assumptions: 
 
75 patients will be randomized to yield 69 evaluable (25 patients per arm) 
 
A one year disease-free survival rate of 60% in the control and 90% in the respective experimental 
groups for an absolute difference of 30% in favor of the experimental treatments 
 
10% drop-out rate 
 
Type I error (alpha) = 0.10 and using a one sided test with no adjustment for multiplicity 
 
Power = 80% to detect a 30% difference in one year disease-free survival between the 
vesigenurtacel-L groups and the control group 
 
Patients are followed for three years after the last patient is enrolled 

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13.0 STUDY CONDUCT CONSIDERATIONS 
13.1 Regulatory and Ethical Considerations 
Heat Biologics will obtain favorable opinion/approval to conduct the study from the appropriate regulatory 
agency in accordance with applicable country-specific regulatory requirements or local regulations where 
applicable prior to a site initiating the study in that country. 
The study will be conducted in accordance with all applicable regulatory requirements, including a US 
IND.  The study will also be conducted in accordance with GCP, all applicable patient privacy requirements, 
and the guiding principles of the Declaration of Helsinki.  This includes, but is not limited to, the following: 
 
IRB/IEC/IBC review and favorable opinion/approval to conduct the study and of any subsequent 
relevant amending documents 
 
Patient informed consent 
 
Investigator reporting requirements 
The sponsor will provide full details of the above either verbally, in writing, or both. 
Written informed consent will be obtained for each patient before he or she can participate in the study. 
13.2 Quality Control (Study Monitoring) 
In accordance with applicable regulations, GCP, and Heat Biologics procedures, Heat Biologics monitors, 
or designee, will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and Heat Biologics requirements. 
Heat Biologics will monitor the study consistent with the demands of the study and site activity to verify 
that the: 
 
Data are authentic, accurate and complete. 
 
Safety and rights of patients are being protected. 
 
Study is conducted in accordance with the currently approved protocol and any other study 
agreements, GCP, and all applicable regulatory requirements. 
 
The investigator agrees to allow the monitor direct access to all relevant documents. 
13.3 Protocol Deviations 
In general, a protocol deviation is an inadvertent excursion to, or non-compliance with, the IRB approved 
protocol.  The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures described in this protocol and should not implement any changes to the protocol unless it is 
required to eliminate an immediate hazard to the patient. 
For the purposes of the protocol, deviations that fall into the following categories will be captured on the 
ECRFs.  If the deviation affects the safety of the patient, the sponsor must be notified immediately.  Other 
deviations outside of these categories will be reported to the IRB in accordance with local requirements, as 
applicable. 

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 
Entered into the study without meeting eligibility criteria 
 
Developed withdrawal criteria during the study and was not withdrawn 
 
Received wrong treatment or incorrect dose 
 
Received excluded concomitant treatment 
 
Failed to collect data necessary to interpret primary endpoints 
13.4 Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, Heat Biologics may conduct 
one or more quality assurance audits.  Regulatory agencies may also conduct regulatory inspection of this 
study.  Such audits/inspections can occur at any time during or after completion of the study.  If an audit or 
inspection occurs, the investigator and institution agree to allow the auditor/inspector direct access to all 
relevant documents and to allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any relevant issues. 
13.5 Study and Site Closure 
Upon completion or premature discontinuation of the study, the monitor will conduct site closure activities 
with the investigator or site staff, as appropriate, in accordance with applicable regulations, GCP, and Heat 
Biologics procedures. 
In addition, Heat Biologics reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe non-compliance.  For 
this multicenter study, this can occur at one or more sites.  If Heat Biologics determines such action is 
needed, Heat Biologics will discuss this with the investigator, including the reasons for taking such action, 
at that time.  When feasible, Heat Biologics will provide advance notification to the investigator, where 
applicable, of the impending action prior to it taking effect. 
Heat Biologics will promptly inform all other investigators, and/or institutions conducting the study if the 
study is suspended or prematurely discontinued for safety reasons.  Heat Biologics will also promptly 
inform the regulatory authorities of the suspension or premature discontinuation of the study and the 
reason(s) for the action.  If required by applicable regulations, the investigator must inform the IEC/IRB 
promptly and provide the reason for the suspension or premature discontinuation. 
13.6 Records Retention 
Following closure of the study, the investigator must maintain all site study records, except for those 
required by local regulations to be maintained by someone else, in a safe and secure location.  The records 
must be maintained to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, 
whenever feasible, to allow any subsequent review of data in conjunction with assessment of the facility, 
supporting systems, and staff.  Where permitted by local laws/regulations or institutional policy, some or 
all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  The investigator must 
assure that all reproductions are legible and are a true and accurate copy of the original and meet 

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accessibility and retrieval standards, including re-generating a hard copy, if required.  Furthermore, the 
investigator must ensure there is an acceptable back up of these reproductions and that an acceptable quality 
control process exists for making these reproductions. 
Heat Biologics will inform the investigator of the time period for retaining these records to comply with all 
applicable regulatory requirements.  The minimum retention time will meet the strictest standard applicable 
to that site for the study, as dictated by any institutional requirements or local laws or regulations, or Heat 
Biologics standards/procedures; otherwise, the retention period will default to 15 years. 
The investigator must notify Heat Biologics of any changes in the archival arrangements, including, but not 
limited to, the following: archival at an off-site facility, transfer of ownership of the records in the event the 
investigator leaves the site. 
13.7 Provision of Study Results and Information to Investigators 
When required by applicable regulations, the investigator signatory for the clinical study report will be 
determined at the time the report is written.  When the clinical study report is completed, Heat Biologics 
will provide the investigator with a full summary of the study results.  The investigator is encouraged to 
share the summary results with the patients, as appropriate.  In addition the investigator will be given 
reasonable access to review the relevant statistical tables, figures, and reports and will be able to review the 
results for the entire study at the Heat Biologics site or other mutually agreeable location. 
13.8 Data Management 
The data collection tool for this study will be Heat Biologics-defined ECRF.  Patient data necessary for 
analysis and reporting will be entered/transmitted into a validated database or data system.  Clinical data 
management will be performed in accordance with applicable Heat Biologics standards and data cleaning 
procedures. 
 

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APPENDIX 1: 
BLADDER CANCER STAGING 
Based on AJCC staging, which can be found at the following URL: 
http://www.cancer.gov/cancertopics/pdq/treatment/bladder/HealthProfessional/page3 
 
These T categories for bladder cancer refer to the primary tumor. 
 
TX: primary tumor cannot be assessed; information not known 
 
TO: no evidence of primary tumor 
 
Ta: noninvasive papillary carcinoma 
 
Tis: noninvasive flat carcinoma, also called flat carcinoma in situ. This means that the disease is still 
localized, or contained within the urothelium layer of the bladder wall. Cancer cells have not invaded the 
deeper layers of bladder wall tissue. 
 
T1: the tumor has grown from the layer of cells lining the bladder into the connective tissue below. It has not 
grown into the muscle layer of the bladder. 
 
T2: tumor has grown into the muscle layer  
o 
T2a: the tumor is in the inner half of the muscle layer 
o 
T2b: the tumor is in the outer half of the muscle layer 
 
T3: tumor has grown through the muscle layer and into the surrounding fatty tissue 
o 
T3a: this spread into the fatty tissue can only be seen with a microscope 
o 
T3b: this spread into the fatty tissue is large enough to be seen on imaging test or to be seen/felt by the 
surgeon 
 
T4: tumor has spread into nearby organs or structures.  It may be growing in the stroma (main tissue) of the 
prostate, the seminal vesicles, uterus, vagina, pelvic wall, or abdominal wall 
Histologic Features of Urothelial Papillary Lesions 
 
Papilloma 
Papillary Neoplasm 
of Low Malignant 
Potential 
Low-grade Papillary Carcinoma 
High-grade Papillary Carcinoma 
Architecture: 
 
 
 
 
Papillae
 
 
 
Organization of 
cells 
Delicate 
 
 
Identical to 
Normal 
Delicate. Occasional 
fused 
 
Polarity identical to 
normal. Any 
thickness.  Cohesive 
Fused, branching, and delicate 
 
 
Predominantly ordered, yet 
minimal crowding and minimal 
loss of polarity. Any thickness.  
Cohesive 
Fused, branching and delicate 
 
 
Predominantly disordered with frequent 
loss of polarity. Any thickness. Often 
discohesive 
Cytology: 
 
 
 
 
Nuclear size 
 
 
Nuclear shape 
 
 
Nuclear 
chromatin 
 
 
Nucleoi 
 
 
Mitoses 
 
Umbrella cells 
Identical to 
Normal 
 
Identical to 
Normal 
 
Fine 
 
 
Absent 
 
 
Absent 
 
Uniformly 
present 
May be uniformly 
enlarged 
 
Elongated, round-
oval, uniform 
 
Fine 
 
 
Absent to 
inconspicuous 
 
Rare, basal 
 
Present 
Enlarged with variation in size 
 
 
Round-oval. Slight variation in 
shape and contour. 
 
Mild variation 
 
 
Usually inconspicuous* 
 
 
Occasionally at any level 
 
Usually present 
Enlarged with variation in size  
 
 
Moderate-marked pleomorphism 
 
 
Moderate-marked variation both within 
and between cells with hyperchromasia 
 
Multiple prominent nucleoli may 
be present 
 
Usually frequent, at any level 
 
May be absent 
*If present, small and regular and not accompanied by other features of high-grade carcinoma. 
 
Note:  Only patients with high-risk disease (T1 and/or high grade and/or CIS) or intermediate-risk 
disease (Ta low grade with at least 3 of the following 4 risk factors: multiple tumors, tumor size >3cm, 
early recurrence (<1 year from previous TURBT), or frequent recurrences (>1 per year)) are eligible for 
participation in the trial.  

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APPENDIX 2: 
STAGES OF HEART FAILURE 
The following stages of heart failure are based on the New York Heart Association (NYHA) functional 
classification 
system 
(taken 
from 
the 
Heart 
Failure 
Society 
of 
America 
http://www.abouthf.org/questions_stages.htm). 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, 
palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable 
at rest, but ordinary physical activity results in 
fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. 
Comfortable at rest, but less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without 
discomfort. Symptoms of cardiac insufficiency at 
rest. If any physical activity is undertaken, 
discomfort is increased. 

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APPENDIX 3: 
GRADING SCALE FOR INJECTION SITE REACTIONS 
The grading scale is derived from the FDA Guidance for Industry 
(http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/vaccin
es/ucm074775.htm#TOXICITYGRADINGSCALETABLES) 
 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially Life 
Threatening 
Pain 
Does not 
interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
Emergency room 
visit or 
hospitalization 
Erythema/Redness 
2.5-5 cm 
5.1-10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling* 
2.5-5 cm and 
does not interfere 
with activity 
5.1-10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
* Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 

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APPENDIX 4: 
PROTOCOL REVISION HISTORY 
 
Protocol Change 
Section Affected 
Version 
where 
implemented 
Change tumor volume collection from mg 
to ug (microns) 
Section 10.1.5 
Version 2.0, 
Amendment 1 
Allow immune monitoring to be either by 
flow cytometry or ELISPOT to determine 
best methodology to advance into Phase 2 
Synopsis and Section 10.1 
Version 2.0, 
Amendment 1 
Add ELISPOT assay details 
Section 10.1.1 
Version 2.0, 
Amendment 1 
Remove the vial label from the protocol 
due to the potential for label changes over 
time 
Appendix 4 
Version 2.0, 
Amendment 1 
Clarify in inclusion criteria that bladder 
risk assessment score must be ≥8 on the 
recurrence scale and ≤ 18 on the 
progression scale 
Synopsis and Sections 4.1 and 6.2.1 
Version 2.0, 
Amendment 1 
Update timing of first dose relative to 
TURBT procedure to be consistent with 
the text elsewhere in the protocol 
Schedule of Events (SOE) 
 Version 2.0, 
Amendment 1 
Change DLT definition such that any AE 
>= Grade 3 that is possibly, probably, or 
definitely related to study drug be 
classified as such.  (Formerly it was only 
"definitely" related items.)  Also 
exceptions for systemic injections now 
ONLY include fever, myalgia, headache, 
or fatigue, nothing additional.  
Section 5.2.1 
Version 2.0, 
Amendment 1 
Modify trial stopping rules such that 
enrollment is stopped and a full safety 
review is conducted if a death occurs 
within 24-hrs of vaccination if it is not 
clearly attributed to another cause.  
(Previously was only if it's definitely 
related).  
Section 5.2.2 
Version 2.0, 
Amendment 1 
Modify statement that sites will be 
provided with optical discs as we will 
only do this upon request 
Section 10.2 
Version 2.0, 
Amendment 1 
Outline definitions of Protocol Deviations 
that will be collected in the CRF and that 
need to be reported to the Sponsor 
Section 12.75 and new section 13.3 
 Version 2.0, 
Amendment 1 
Add section for definitions of ECG 
parameters as a listed procedure 
Between former sections 11.3 and 11.4 - 
new section becomes Section 11.4 
Version 2.0, 
Amendment 1 
Fix formatting of bullet points around 
relatedness of AEs 
Former section 11.7.5 - new numbering 
Section 11.8.5 
Version 2.0, 
Amendment 1 

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Protocol Change 
Section Affected 
Version 
where 
implemented 
Add "recovered / resolved" to AE event 
outcomes 
Former section 11.7.5 - new numbering 
Section 11.8.5 
Version 2.0, 
Amendment 1 
Change definition of time to recurrence to 
be relative to the date of randomization 
rather than the date of dosing 
Section 12.5.2 
Version 2.0, 
Amendment 1 
Remove immune response lab at 
Screening 
SOE and Section 6.1 
Version 2.0, 
Amendment 1 
Remove requirement in footnote 1 of the 
SOA that requires screening labs to be 
done within 2 weeks of  dose, since these 
labs will be redone at BL if the screening 
labs were taken more than 3 days prior to 
first dose 
SOE 
Version 2.0, 
Amendment 1 
Update Week 7 and schedule of events 
window should be +/- 1 
Section 6.2.3 
Version 2.0, 
Amendment 1 
Modify language from "pulse" to "heart 
rate" in the section on vital signs to be 
consistent with the rest of the protocol 
Section 12.7.3 
Version 2.0, 
Amendment 1 
Combine "persistent disease" and 
"recurrent disease" and "progressive 
disease" into "evidence of disease" rather 
than separate categories since we can't tell 
them apart.   
Synopsis, sections 3.1, 3.4, 6.2.3, 7.2.2, 
12.2, 12.3, 12.6.3, SOE 
Version 2.0, 
Amendment 1 
Revise language in "dosing regimen" and 
"route" section to avoid duplication 
between the two and include clearer 
dosing for each cohort.  
Synopsis 
Version 2.0, 
Amendment 1 
Add study schema to visually represent 
the overall design 
Section 3.1 
Version 2.0, 
Amendment 1 
Add Sponsor protocol approval page 
Front 
Version 2.0, 
Amendment 1 
Allow tumor curls or slides or fresh 
frozen tissue instead of FFPE and  if 
necessary 
Synopsis and Sections 6.2.1, 6.2.3, 6.2.7, 
6.3, 10.1.5 
Version 2.0, 
Amendment 1 
Clarify that proteomics and recurrence 
rate comparison to placebo will only be 
done in the Phase 2 portion 
Synopsis and Section 2.2 
Version 2.0, 
Amendment 1 
Clarify number of patients that will be 
enrolled 
Synopsis and Section 3.4 
Version 2.0, 
Amendment 1 
Clarify that patients who discontinue 
vaccine at Week 7 due to evidence of 
disease will continue in long-term follow-
up 
Section 6.2.3 and SOE 
Version 2.0, 
Amendment 1 

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Protocol Change 
Section Affected 
Version 
where 
implemented 
Switch ordering of Appendix 2 and 3 and 
update references to each 
Synopsis, section 4.1, Appendix 2 and 3 
Version 2.0, 
Amendment 1 
Correct "possible" to "possibly" in section 
defining dose limiting toxicities 
Section 5.2.1 
Version 3.0, 
Amendment 2 
Add DLT escalation rules (eg if 1 of 9 
patients get DLT we'll escalate, if 2/9 do, 
we'll stop).   
Section 5.2.1 
Version 3.0, 
Amendment 2 
Remove reference on bottom of page 30 
to additional backup sample for immune 
response timepoint (lingering error from 
previous version of protocol) 
Section 6.1 
Version 3.0, 
Amendment 2 
Clarify that eye exam involves evaluation 
for dry eyes 
Section 11.5 
Version 3.0, 
Amendment 2 
Remove risk assessment tool 
Synopsis, Section 4.1, Section 6.2.1, 
SOE, Appendix 3,  
Version 3.0, 
Amendment 2 
Remove requirement that all injections 
occur with same needle. 
Section 8.3.1 
Version 3.0, 
Amendment 2 
Rearrange synopsis content for clarity 
Synopsis 
Version 3.0, 
Amendment 2 
Update product description to allow for 
revised formulation to be implemented 
without additional protocol amendment 
Synopsis, Section 8.1 
Version 3.0, 
Amendment 2 
Clarify language in dosing administration 
around injection site rotation 
Synopsis, Section 8.3.1 
Version 3.0, 
Amendment 2 
Note that missed doses will not be made 
up 
Section 8.3.1 
Version 3.0, 
Amendment 2 
Combine DEC and DSMB into a single 
entity 
List of Abbreviations, Synopsis, Section 
5.1.2 
Version 3.0, 
Amendment 2 
Switch to single blinding (physician-
patient) 
Synopsis, Sections 3.1, 5.3, 6.4 
Version 3.0, 
Amendment 2 
Clarify definition of primary endpoint in 
Phase 1 as an increase of 2-fold over 
baseline in IFN-secreting CD8+ T cells 
Synopsis, Section 3.5.1 
Version 3.0, 
Amendment 2 
Switch primary endpoint in Phase 2 from 
Time to Recurrence to Disease Free 
Survival to eliminate death as a 
competing risk and to include disease 
progression as well as disease recurrence; 
remove PFS as a secondary endpoint 
since DFS replaces it 
Synopsis, Sections 2.1, 2.2, 3.5.1, 3.5.2,  
Version 3.0, 
Amendment 2 
Replace blood sampling for proteomic 
analysis with blood banking for future 
analyses 
Synopsis, Sections 2.2, 3.5.2, 6.2.1, 
6.2.5, 6.2.9, SOE, 12.4.1, 12.4.2,  
Version 3.0, 
Amendment 2 

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Protocol Change 
Section Affected 
Version 
where 
implemented 
Delete section 12.4 due to duplicity with 
section 3.5 
Sections 12.4, 12.4.1, 12.4.2 
Version 3.0, 
Amendment 2 
Clarify that an overage of patients has 
been included in the sample size and that 
patients will not be replaced 
Sections 3.1, 3.4, 7.2.2, 12.2 
Version 3.0, 
Amendment 2 
Remove reference to temperature 
monitoring device due to detailed 
description in pharmacy manual 
Section 8.4.3 
Version 3.0, 
Amendment 2 
Remove batch number from the label 
Section 8.4.2 
Version 3.0, 
Amendment 2 
Revisions to the statistical sections 
(analysis populations, sample size 
justification) etc.   
Synopsis, Sections 12.X 
Version 3.0, 
Amendment 2 
Revise the dose escalation process such 
that the DEC will convene after at least 
one patient has received 6 vaccine doses 
and at least three patients have received 
two doses.   
Synopsis, Sections 3.1, 5.1.1 
Version 3.0, 
Amendment 2 
Extend window of beginning of treatment 
from 8-10 weeks post-TURBT to 8-12 
week post-TURBT. 
Synopsis, SOE, Section 3.1 
Version 3.0, 
Amendment 2 
Change "enrollment" to "dosing" in 
description of dose escalation for clarity 
Synopsis, Section 3.1, 5.2.2 
Version 3.0, 
Amendment 2 
Add detail in Appendix 2 to provide 
additional clarity about staging 
requirement  
Appendix 2 
Version 3.0, 
Amendment 2 
Remove section 3.3 as duplicative to 
section 3.1 
Section 3.3 
Version 3.0, 
Amendment 2 
Change regimen in Phase 1 and Phase 2 
Synopsis, Section 3.1, Section 6.0, 
Section 8.5, Section 12.1 
Version 4.0, 
Amendment 3 
Define a BCG maintenance schedule 
Synopsis, Section 3.1, Section 8.5.1, 
Section 8.5.2 
Version 4.0, 
Amendment 3 
Allow a single post-TURBT instillation 
of intravesical chemotherapy 
Section 9.1 
Version 4.0, 
Amendment 3 
Analyze recurrence separately from 
progression 
Section 10.1 
Version 4.0, 
Amendment 3 
Define persistent disease for patients with 
CIS 
Section 10.1 
Version 4.0, 
Amendment 3 
Define the dose of BCG 
Section 8.4, Section 8.5.2 
Version 4.0, 
Amendment 3 
Modify window between TURBT and 
start of treatment 
Synopsis, Section 3.1, Section 6.2.1 
Version 4.0, 
Amendment 3 

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Protocol Change 
Section Affected 
Version 
where 
implemented 
Require 5 of 6 cycles of induction BCG 
Section 8.4 
Version 4.0, 
Amendment 3 
Changed criteria for CrCl, albumin, and 
platelet laboratory parameters 
Synopsis, Section 4.1 
Version 4.0, 
Amendment 3 
Adopt the standard definition of high-risk 
disease (T1 and/or high grade and/or CIS) Synopsis, Section 4.1, Appendix 1 
Version 4.0, 
Amendment 3 
Exclude patients with prior prostatic 
pelvic radiation within the past 12 months Synopsis, Section 4.2 
Version 4.0, 
Amendment 3 
Exclude patients with neo-adjuvant 
therapy prior to the most recent TURBT 
Synopsis, Section 4.2 
Version 4.0, 
Amendment 3 
Exclude patients with allergy to peanuts 
Synopsis, Section 4.2 
Version 4.0, 
Amendment 3 
Reduce time window for cardiac 
exclusion from previous 6 months to 3 
months 
Synopsis, Section 4.2, Appendix 2 
Version 4.0, 
Amendment 3 
Move directly to Phase 2 after cohort 1 in 
Phase 1 
Synopsis, Section 3.1, Section 5.1, 
Section 6.2 
Version 4.0, 
Amendment 3 
Take immune response off the decision-
tree and advance both doses into Phase 2 
Synopsis, Section 3.1, Section 5.1, 
Section 6.2 
Version 4.0, 
Amendment 3 
Keep patients without progression or T1 
high-grade disease on trial until 6 months 
even if evidence of disease 
Synopsis, Section 3.1, Section 6.1, 
Section 6.2, Section 10.1 
Version 4.0, 
Amendment 3 
Add endpoints for recurrence at 6, 12, 18, 
and 24 months; DFS at 6, 18, and 24 
months; overall DFS; repeat TURBT by 
12 and 24 months; cystectomy by 12 and 
24 months.  Add 6-mo CR endpoint 
Synopsis, Section 3.4.2, Section 12.5.2 
Version 4.0, 
Amendment 3 
Change primary endpoint in Phase 1 to 
safety and tolerability 
Synopsis, Section 3.4.1 
Version 4.0, 
Amendment 3 
Change primary endpoint in Phase 2 to 1-
yr DFS 
Synopsis, Section 3.4.1, Section 12.5.1.1 
Version 4.0, 
Amendment 3 
Change title 
Cover page, Sponsor Protocol Approval 
page, Investigator Protocol Agreement 
page, Synopsis 
Version 4.0, 
Amendment 3 
Clarify definition of recurrence events  
Section 10.1 
Version 4.0, 
Amendment 3 
Allow a subset of intermediate risk 
patients 
Synopsis, Section 4.1, Appendix 1 
Version 4.0, 
Amendment 3 
Add stratification factors for intermediate 
vs. high risk and presence of CIS 
Synopsis, Section 8.5 
Version 4.0, 
Amendment 3 
Update introduction 
Section 1.1, Section 1.2 
Version 4.0, 
Amendment 3 

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Protocol Change 
Section Affected 
Version 
where 
implemented 
Update Sponsor address and Medical 
Monitor 
Contact Page 
Version 4.0, 
Amendment 3 
Change sample size 
Synopsis, Section 3.3, Section 12.6 
Version 4.0, 
Amendment 3 
Fix typos, abbreviations, punctuation and 
spacing 
Throughout 
Version 4.0, 
Amendment 3 
Add safety objective for Phase 2 
Synopsis, 2.2 Secondary Objectives, 
12.5.2 Analysis of Secondary Efficacy 
Parameters 
Version 5.0, 
Amendment 4 
Allow patients who have had fulguration 
or no surgery if they have CIS alone 
Synopsis, 2.2 Secondary Objectives, 3.1 
Study Design Overview, 4.1 Inclusion 
Criteria 
Version 5.0, 
Amendment 4 
Update Immune Response methodology, 
objectives, and endpoints 
Synopsis, 2.2 Secondary Objectives, 
3.4.2 Secondary Endpoints, 10.2 
Immunolgic Response, 12.5.2.9 Immune 
Response 
Version 5.0, 
Amendment 4 
Remove blood sample for banking 
6.2 Phase 2 
Version 5.0, 
Amendment 4 
Increase blood collected for Immunologic 
Response 
6.2.1 Phase 2 Schedule of Events, 10.2 
Immunologic Response 
Version 5.0, 
Amendment 4 
Remove specific dose information for 
BCG 
Synopsis, 8.4 Dosage and Administration 
of BCG 
Version 5.0, 
Amendment 4 
Update sample size assessment 
assumptions (removed event and 
censoring times follow an exponential 
distribution) 
12.6.2 Phase 2 
Version 5.0, 
Amendment 4 
Add fulguration at 12 and 24 months to 
secondary and exploratory 
objectives/endpoints 
Synopsis, 2.2 Secondary Objectives, 
3.4.2 Secondary Endpoints, 12.5.2.7 
Proportion of patients undergoing post-
treatment TURBT or fulguration by 12 
and 24 months, 12.5.2.10 Exploratory 
Endpoints 
Version 5.0, 
Amendment 4 
Change most-recent TURBT procedure to 
baseline staging procedure 
Throughout 
Version 5.0, 
Amendment 4 
Update creatinine clearance requirement 
Synopsis, 4.1 Inclusion Criteria 
Version 5.0, 
Amendment 4 
Combine Removal of Patients from 
Treatment with Discontinuation from 
Study Treatment 
Section 7.2.1 
Version 5.0, 
Amendment 4 
Indicate preference for tissue sections 
rather than FFPE 
6.1 Phase 1, 6.2 Phase 2 
Version 5.0, 
Amendment 4 
Wrote out assessments for Weeks 37 and 
49 in Phase 2 
6.2.3.10 and 6.2.3.11 
Version 5.0, 
Amendment 4 

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Protocol Change 
Section Affected 
Version 
where 
implemented 
Update Figure 2 
8.5.1 Schedule and Duration of 
Treatment 
Version 5.0, 
Amendment 4 
Remove frequency of liquid nitrogen 
replacement 
8.6.3 Storage 
Version 5.0, 
Amendment 4 
Update CTCAE version to 4.03 
11.0 Safety Assessments 
Version 5.0, 
Amendment 4 
Allow anti-allergics, antipyretics, and/or 
analgesics for local and/or systemic 
injection reactions 
9.1 Permitted Medications and Non-
Drug Therapies 
Version 5.0, 
Amendment 4 
Updated discontinuation language so that 
patients with evidence of disease may 
continue to receive treatment if in the 
patient’s best interest at the investigator’s 
discretion 
Synopsis, 3.1 Study Design Overview, 
6.1.1 Phase 1 Schedule of Events, 6.1.3.3 
Phase 1 Assessments at Week 7, 6.1.3.7 
Phase 1 Assessments at Week 21, 6.2.1 
Phase 2 Schedule of Events, 6.2.3.5 
Phase 2 Assessments at Week 13, 6.2.3.7 
Phase 2 Assessments at Week 25, 
6.2.3.10 Phase 2 Assessments at Week 
37, 6.2.3.11 Phase 2 Assessments at 
Week 49, 7.2.1 Discontinuation from 
Study Treatment 
Version 5.0, 
Amendment 4 
Include exploratory analysis to pool both 
vaccine groups in Phase 2 
Synopsis, 12.1 General Statistical 
Considerations, 12.5.1.1 1-year Disease-
Free Survival 
Version 5.0, 
Amendment 4 
Increased non-heparinzed blood sample 
to 10mL 
10.2 Immunologic Response 
Version 5.0, 
Amendment 4 
Removed magnesium laboratory 
11.2 Clinical Laboratory Tests 
Version 5.0, 
Amendment 4 
Added analysis of urine immunology 
Synopsis, 2.2 Secondary Objectives, 
3.4.2 Secondary Endpoints, 6.2.1 Phase 2 
Schedule of Events, 6.2.3.1 Phase 2 
Baseline Assessments, 6.2.3.3 Phase 2 
Assessments at Week 7, 6.2.3.5 Phase 2 
Assessments at Week 13, 6.2.3.9 Phase 2 
Assessments at Week 28, 6.2.3.13 Phase 
2 Week 56, 10.2 Immunologic Response 
Version 5.0, 
Amendment 4 
Exclude patient with any condition 
requiring active steroid or other 
immunosuppressive therapy 
Synopsis, 4.2 Exclusion Criteria 
Version 5.0, 
Amendment 4 
Exclude patients with prior treatment 
with a cancer vaccine 
Synopsis, 4.2 Exclusion Criteria 
Version 5.0 
Amendment 4 
Current serious cardiac arrhythmia no 
longer exclusionary 
Synopsis, 4.2 Exclusion Criteria 
Version 5.0, 
Amendment 4 
Collect information on caffeine 
consumption 
9.1 Permitted Medications and Non-
Drug Therapies 
Version 5.0, 
Amendment 4 

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Protocol Change 
Section Affected 
Version 
where 
implemented 
Allow patients who had a radical 
prostatectomy with detectable PSA below 
the definition of biochemical recurrence 
per the Phoenix criteria and no radiologic 
evidence of metastatic disease or with 
PSA doubling time greater than one year 
and no evidence of metastases with no 
active therapy  
Synopsis, 4.2 Exclusion Criteria 
Version 5.0, 
Amendment 4 
Added Heat Biologics logo 
Cover page 
Version 5.0, 
Amendment 4 
Updated HS-410 to vesigenurtacel-L 
Throughout 
Version 5.0, 
Amendment 4 
Updated vesigenurtacel-L or placebo to 
blinded study product 
Throughout 
Version 5.0, 
Amendment 4 
Updated Grade 4 adverse event to 
probably or definitely related to study 
product 
7.2.1 Discontinuation from Study 
Treatment 
Version 5.0, 
Amendment 4 
Added new section on discontinuation 
from study follow-up with text from 7.2.1 
7.2.2 Discontinuation from Study 
Follow-Up 
Version 5.0, 
Amendment 4 
Added new section on discontinuation 
from study follow-up with text from 7.2.1 
7.2.3 Lost to Follow-Up 
Version 5.0, 
Amendment 4 
Changed preparation of vesigenurtacel-L 
to manufacturing of vesigenurtacel-L 
8.1 Description of Investigational 
Product, Vesigenurtacel-L 
Version 5.0, 
Amendment 4 
Indicated that site must contact IWRS for 
assignment of the dose vial at each dosing 
8.3 Dosage and Administration of 
Vesigenurtacel-L and Placebo 
Version 5.0, 
Amendment 4 
Indicated that vesigenurtacel-L must be 
stored at ≤ -120C 
8.6.3 Storage 
Version 5.0, 
Amendment 4 
Clarify that no investigational agents 
allowed during treatment but no 
prohibited medications during follow-up 
9.2 Prohibited Medications and Non-
Drug Therapies 
Version 5.0, 
Amendment 4 
Added IBCG and AJCC 
List of Abbreviations 
Version 5.0, 
Amendment 4 
Added ISR Grading Scale 
New Appendix 3 and 11.6 Injection Site 
Reactions 
Version 5.0, 
Amendment 4 
Removed reference to Post-Study AEs 
and SAEs chapter in the study manual 
11.7.2 Action to Be Taken if Pregnancy 
Occurs 
Version 5.0, 
Amendment 4 
Added definition of safety for Phase 1 
12.4.6 Safety of Vesigenurtacel-L (Phase 
1 Only) 
Version 5.0, 
Amendment 4 
Updated definition of safety for Phase 2 
and moved from 12.5.2.1 to 12.4.7 
12.4.7 Safety of the Combination of 
Vesigenurtacel-L and BCG (Phase 2 
Only) 
Version 5.0, 
Amendment 4 

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Protocol Change 
Section Affected 
Version 
where 
implemented 
Stated that staging is based on AJCC 
Appendix 1 
Version 5.0, 
Amendment 4 
Updated serum creatinine to 2.2 mg/dL 
or calculated creatinine clearance > 35 
mL/minute per the Cockcroft-Gault 
formula 
Synopsis, 4.1 Inclusion Criteria 
Version 5.0, 
Amendment 4 
Increased total sample size from 84 to 
110, the number of patients in Phase 1 
from 9 to 10, and the number of patients 
in Phase 2 from 75 to 100 
Synopsis, 3.3 Number of Subjects, 
6.4 Blinding and Minimization of Bias  
Version 6.0 
Amendment 5 
Added a fourth treatment arm in Phase 2; 
patients who will not receive BCG will be 
enrolled in an open-label arm and receive 
12 weeks of high dose vesigenurtacel-L 
followed by 3 courses of 3 once-weekly 
vaccine injections 3, 6, and 12 months 
after beginning vaccine therapy 
Synopsis, 3.0 Trial Design, 
5.3 Emergency Unblinding of Treatment 
Assignment, 6.0 Study Procedures, 
8.5 Treatment Assignment 
Version 6.0 
Amendment 5 
Updated the statistical analysis given the 
fourth treatment arm in Phase 2 
Synopsis, 12.1 General Statistical 
Considerations, 12.2 Analysis 
Populations, 12.4.6 Safety of 
Vesigenurtacel-L, 12.4.7 Safety of the 
Combination of Vesigenurtacel-L and 
BCG, 12.5 Efficacy Analysis, 
12.6 Sample Size Estimations 
Version 6.0 
Amendment 5 
Cystoscopy/cytology and long-term 
follow-up will occur every 3 months for 
the first 2 years of follow up, then every 6 
months for up to a year 
Synopsis, 3.1 Study Design Overview, 
6.1 Phase 1, 6.2 Phase 2 Schedule of 
Events, 6.3 Long-term Follow-up, 
10.1 Evaluation of Disease 
Version 6.0 
Amendment 5 
Updated the per protocol population 
definition 
12.2 Analysis Populations 
Version 6.0 
Amendment 5 
Updated the exclusion criteria on active 
malignancies in the past 12 months, 
added an exclusion for prior vaccination 
with BCG for tuberculosis, and added an 
exclusion for prior splenectomy 
Synopsis, 4.2 Exclusion Criteria 
Version 6.0 
Amendment 5 
Increased the number of trial centers from 
up to 17 to up to 20 
Synopsis, 3.3 Number of Subjects 
Version 6.0 
Amendment 5 
Added background information on BCG 
timing, the current BCG shortage, and 
immunotherapy in the setting of minimal 
residual disease 
1.1 Bladder Cancer 
Version 6.0 
Amendment 5 
Included possible synergy between 
inflammation from surgery and 
vesigenurtacel-L 
1.2 Rationale for Vesigenurtacel-L 
Development 
Version 6.0 
Amendment 5 

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Investigational Product: Vesigenurtacel-L 
Protocol HS410-101 
 
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Version 8.0; 03 Feb 2016 
 
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Protocol Change 
Section Affected 
Version 
where 
implemented 
Updated Figures 1 and 2 
3.1 Study Design Overview, 8.5.1 
Schedule and Duration of Treatment 
Version 6.0 
Amendment 5 
Allow patients with evidence of disease 
to continue on treatment longer than the 
next assessment if judged by the 
investigator to be in the patient’s best 
interest 
Synopsis, 3.0 Trial Design, 6.1 Phase 1, 
6.2 Phase 2, 10.1 Evaluation of Disease 
Version 6.0 
Amendment 5 
Replaced AE wording “possibly, 
probably or definitely related” with 
“related” 
5.2.1 Dose Limiting Toxicities, 5.2.2 
Trial Stopping Rules, 6.1.1 Phase 1 
SOA, 6.2.1 Phase 2 SOA, 11.8 AE and 
SAE, 11.8.5 Reporting AE 
Version 6.0 
Amendment 5 
Due to batch release delays of certain 
doses of vaccine, the randomization 
schedule has been revised.  
Synopsis, 3.0 Trial Design, 5.1 Data 
Monitoring Committee, 6.4 Blinding and 
Minimization of Bias, 8.5 Treatment 
Assignment, 12.2 Analysis Populations, 
12.6 Sample Size Estimations 
Version 7.0 
Amendment 6 
Added abbreviation of DMSO 
Synopsis, List of Abbreviations 
Version 7.0 
Amendment 6 
No longer specify number of injections or 
dose per vial of product 
Synopsis; 3.2 Justification of Study 
Product Administration; 6.1.1 Phase 1 
Schedule of Events; 6.2.1 Phase 2 
Schedule of Events; 8.1 Description of 
Investigational Product, Vesigenurtacel-
L; 8.3 Dosage and Administration of 
Vesigenurtacel-L and Placebo 
Version 7.0 
Amendment 6 
Removed excipient percentages for 
placebo 
8.2 Description of Placebo 
Version 7.0 
Amendment 6 
Removed references to UM-UC-3 cell 
line; added PC3 cell line 
1.2 Rationale for Vesigenurtacel-L 
Development; 1.3 Description of 
Investigational Agent Vesigenurtacel-L 
Version 8.0 
Amendment 7 
Revised Statistical Analysis methods to 
match Statistical Analysis Plan 
12.0 Statistical Considerations 
Version 8.0 
Amendment 7 
Removed direct reference to TCR 
sequencing vendor 
10.2.4 TCR Sequencing 
Version 8.0 
Amendment 7 
 

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Protocol HS410-101 
 
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REFERENCES 
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Protocol HS410-101 
 
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