A Phase 2, Multicenter, Single-Arm Trial of CV301 in Combination With PD-1/L1 Blockade in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer
Phase: PHASE2
Conditions: Bladder Cancer
Sponsor: Bavarian Nordic

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CV301-BLD-001 
 
A Phase 2, Multicenter, Single-Arm Trial of CV301 in 
Combination with PD-1/L1 Blockade in Patients with 
Locally Advanced or Metastatic Urothelial Bladder 
Cancer 
 
 
Clinical Trial Protocol Edition 2.0 
 
 
28-Mar-2019 
 
Revision Chronology 
Protocol Edition 
Date 
Version 
Edition 1.0 
16-Feb-2018 
Original 
Edition 2.0 
28-Mar-2019 
Amendment 1 
Refer to Section 17.5 for details 
 
NCT03628716

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1 General Information 
1.1 Investigator Signature Page 
Herewith I agree that I have read and fully understand this protocol: 
A Phase 2, Multicenter, Single-Arm Trial of CV301 in combination with PD-1/L1 blockade 
in Patients with Locally Advanced or Metastatic Urothelial Bladder Cancer 
This protocol describes necessary information to conduct the trial. I agree that I will conduct the 
trial according to the instructions given within this protocol. Furthermore, I agree that I will 
conduct this trial according to International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP), the 2013 version of the Declaration of Helsinki, as well as applicable local legal and 
regulatory requirements in the respective countries. I agree that all information revealed in this 
protocol is handled strictly confidentially. 
Additionally, I will permit trial related monitoring, audits, Institutional Review Board (IRB) 
review and regulatory inspections, providing direct access to source data/documents. 
 
 
 
 
 
 
 
 
(Date) 
 
(Signature)  [Name, Department] 

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1.3 Responsibilities 
Trial Number 
 
CV301-BLD-001 
 
 
 
Title 
 
A Phase 2, Multicenter, Single-Arm Trial of CV301 in 
Combination with PD-1/L1 Blockade in Patients with 
Locally Advanced or Metastatic Urothelial Bladder 
Cancer 
 
 
 
Sponsor and Product 
Supply 
 
 
Phone 
 
Fax 
 
Website 
 
 
 
Project Leader 
 
Phone 
 
E-mail 
 
 
 
Medical Monitor 
 
Phone  
 
E-mail 
 
 
 
Pharmacovigilance 
 
Phone  
 
E-mail 
 
 
 
 
 

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Table of Contents 
 
1 
General Information ........................................................................................ 2 
1.1 Investigator Signature Page ............................................................................. 2 
1.2 Sponsor Signature Page ................................................................................... 3 
1.3 Responsibilities .................................................................................................. 4 
List of Tables ........................................................................................................... 10 
List of Figures ......................................................................................................... 10 
List of Abbreviations .............................................................................................. 11 
1.4 Protocol Synopsis ............................................................................................ 16 
1.5 Trial Procedure Schedule............................................................................... 27 
2 
Background Information and Scientific Rationale ..................................... 30 
2.1 Introduction ..................................................................................................... 30 
2.2 Trial Rationale ................................................................................................ 33 
2.3 MVA-BN-CV301 & FPV-CV301 Vaccine(s) ................................................ 34 
2.3.1 
Origin and Characteristics of MVA-BN Vector Backbone ..................... 34 
2.3.2 
Clinical Experience with MVA-BN and Recombinant MVA-based 
Vaccines ........................................................................................................ 35 
2.3.3 
Safety Overview of MVA-BN and Recombinant MVA-based 
Vaccines ........................................................................................................ 36 
2.4 Overview of Fowlpox virus (FPV) ................................................................. 37 
2.4.1 
Recombinant Poxvirus-based Vaccines Including Fowlpox-based 
Vaccines ........................................................................................................ 38 
2.5 Overview of the Predecessor Product PANVAC ......................................... 38 
2.5.1 
PANVAC-Early “First-Generation” Vaccine ........................................... 38 
2.5.1.1 
Safety Overview of PANVAC....................................................................39 
2.6 CV301 Next Generation Product Following PANVAC .............................. 40 
2.7 Trial Population .............................................................................................. 41 

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2.8 Risk/Benefit Assessment ................................................................................. 42 
2.8.1 
Potential Risks ............................................................................................. 42 
2.8.2 
Benefits ......................................................................................................... 43 
3 
Objectives ........................................................................................................ 44 
4 
Trial Design ..................................................................................................... 44 
4.1 Experimental Design ...................................................................................... 44 
4.2 Description of Trial Procedure ...................................................................... 45 
4.2.1 
Screening Phase ........................................................................................... 45 
4.2.2 
Active Trial Phase ....................................................................................... 46 
4.2.2.1 
Randomization ............................................................................................46 
4.2.2.2 
Visit Description .........................................................................................46 
4.2.3 
Long Term Follow-up Period ..................................................................... 48 
4.2.4 
Unscheduled Visits ...................................................................................... 48 
4.2.5 
Premature Discontinuation ........................................................................ 48 
4.2.5.1 
Discontinuation from Treatment ..............................................................48 
4.2.5.2 
Discontinuation from Long Term Follow-up ..........................................49 
4.3 Trial Duration ................................................................................................. 49 
4.4 Safety Monitoring Team ................................................................................ 50 
4.5 Data and Safety Monitoring Board ............................................................... 50 
4.6 Trial Halting Rules ......................................................................................... 50 
4.6.1 
Safety Halting Rules .................................................................................... 50 
4.6.2 
Efficacy Halting Rules ................................................................................. 51 
5 
Selection of Subjects ....................................................................................... 51 
5.1 Recruitment Procedure .................................................................................. 51 
5.2 Inclusion Criteria ............................................................................................ 52 
5.3 Exclusion Criteria ........................................................................................... 52 
6 
Investigational Medicinal Product ............................................................... 52 
6.1 MVA-BN-CV301 ............................................................................................. 52 

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6.2 FPV-CV301...................................................................................................... 52 
6.3 Atezolizumab (Tecentriq ®) ............................................................................ 52 
6.4 Production, Packaging and Labeling ............................................................ 53 
6.5 Shipment, Storage and Handling .................................................................. 53 
6.6 Preparation, Administration and Dosage ..................................................... 54 
6.7 Accountability and Disposal .......................................................................... 54 
7 
Blood and Tissue Collection for Correlative Biomarker Studies for 
Exploratory Analyses ..................................................................................... 54 
7.1 Collection of Blood Samples .......................................................................... 55 
7.2 Collection of Tumor Tissue ............................................................................ 55 
7.3 Exploratory Analyses ..................................................................................... 55 
7.4 Future Use of Lab Specimen .......................................................................... 56 
8 
Safety ............................................................................................................... 56 
8.1 Definitions ........................................................................................................ 57 
8.1.1 
Medical History ........................................................................................... 57 
8.1.2 
Adverse Events ............................................................................................ 57 
8.1.3 
Adverse Event of Special Interest (AESI) ................................................. 57 
8.1.4 
Serious Adverse Events ............................................................................... 58 
8.2 Assessment ....................................................................................................... 60 
8.2.1 
Relevant Medical History ........................................................................... 60 
8.2.2 
Prior and Concomitant Medication ........................................................... 60 
8.2.2.1 
Permitted Medications ...............................................................................60 
8.2.2.2 
Prohibited Medications ..............................................................................61 
8.2.3 
Physical Examination .................................................................................. 61 
8.2.4 
Vital Signs .................................................................................................... 62 
8.2.5 
AEs ................................................................................................................ 62 
8.2.5.1 
Progression of Underlying Malignancy ....................................................62 
8.2.6 
Cardiac Assessment ..................................................................................... 63 

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8.2.7 
Safety Laboratory Measurements ............................................................. 63 
8.2.8 
Pregnancy ..................................................................................................... 64 
8.3 Reporting ......................................................................................................... 65 
8.3.1 
Reporting of SAE ......................................................................................... 65 
8.3.2 
Reporting of AESIs ..................................................................................... 66 
8.3.3 
Reporting of Pregnancies ............................................................................ 66 
9 
Statistical Considerations .............................................................................. 67 
9.1 Endpoints ......................................................................................................... 67 
9.2 Sample Size Calculation ................................................................................. 67 
9.3 Analysis Populations ....................................................................................... 67 
9.4 Subject Disposition ......................................................................................... 68 
9.5 Subject Characteristics .................................................................................. 68 
9.6 Prior/Concomitant Medications .................................................................... 68 
9.7 Efficacy Analysis ............................................................................................. 68 
9.7.1 
Primary Efficacy Analysis .......................................................................... 68 
9.7.2 
Secondary Efficacy Analyses ...................................................................... 69 
9.7.2.1 
Progression-Free Survival .........................................................................69 
9.7.2.2 
Overall Survival ..........................................................................................70 
9.7.2.3 
Duration of Response .................................................................................70 
9.7.3 
Subgroup Analyses ...................................................................................... 71 
9.8 Exploratory Analyses ..................................................................................... 71 
9.9 Safety Analysis ................................................................................................ 71 
9.9.1 
Adverse Events ............................................................................................ 71 
9.9.2 
Laboratory Data .......................................................................................... 72 
9.9.3 
Treatment Exposure .................................................................................... 72 
9.10 Multiplicity ...................................................................................................... 72 
9.11 Interim Analysis .............................................................................................. 73 
9.12 Timing of Analyses ......................................................................................... 74 

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9.13 Changes in Statistical Methods ..................................................................... 74 
10 
Ethical Aspects ................................................................................................ 74 
10.1 Ethical and Legal Regulations ....................................................................... 74 
10.2 Approved by IRB ............................................................................................ 75 
10.3 Confidentiality and Data Protection ............................................................. 75 
11 
Informed Consent ........................................................................................... 76 
12 
eCRF and Retention of Records ................................................................... 77 
12.1 eCRF ................................................................................................................ 77 
12.2 Retention of Records ...................................................................................... 77 
13 
Monitoring of the Trial .................................................................................. 78 
14 
Audits and Inspections ................................................................................... 78 
15 
Responsibility of the Investigators ................................................................ 79 
16 
References ....................................................................................................... 80 
17 
Appendices ...................................................................................................... 87 
17.1 Appendix 1: Contraception Eligibility Criteria for Female and Male 
Subjects ............................................................................................................ 87 
17.2 Appendix 2: NCI Common Terminology Criteria For Adverse Events 
(NCI CTCAE version 5). ................................................................................ 88 
17.3 Appendix 3: Algorithm for Reporting of AESIs .......................................... 89 
17.4 Appendix 4: RECIST 1.1 Criteria ................................................................. 90 
17.5 Appendix 5: Protocol Changes ...................................................................... 91 

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List of Tables 
Table 1: 
Adequate Organ Function Laboratory Values ................................................... 19 
Table 2:  
Summary of Approved Anti- PD-1/PD-L1 Antibodies for Urothelial 
Cancer ..................................................................................................................... 31 
Table 3:  
Summary of CEA and MUC-1 Expression Levels in Urothelial Bladder 
Cancer ..................................................................................................................... 34 
Table 4: 
Protocol Required Safety Laboratory Assessments ............................................ 63 
 
 
List of Figures 
Figure 1: 
Interim Analysis Decision Tree ............................................................................. 73 
 
 
 

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List of Abbreviations 
 
anti-TNF 
anti-Tumor-Necrosis Factor 
aPTT 
Activated Partial Thromboplastin Time  
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ADR 
Adverse Drug Reaction 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count  
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BCG 
Bacillus Calmette-Guérin 
BN 
Bavarian Nordic 
BUN 
Blood Urea Nitrogen 
CEA 
Carcinoembryonic Antigen 
CI 
Confidence Interval 
CNS 
Central Nervous System 
COPD 
Chronic Obstructive Pulmonary Disease 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte-associated Protein 4 
DDMVAC 
Dose-dense Methotrexate, Vinblastine, Doxorubicin and Cisplatin 
dL 
Deciliter 
DILI 
DrugInduced Liver Injury 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 

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EDC 
Electronic Data Capture 
EE 
Efficacy Evaluable Set 
EMA 
European Medicines Agency 
EMR 
Electronic Medical Record 
EOT 
End of Treatment 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed Paraffin-embedded  
FPV 
Fowlpox Virus 
FU 
Follow-Up 
GC 
Gemcitabine plus Cisplatin 
GCP 
Good Clinical Practice 
g 
Grams  
HBcAb 
Hepatitis B Core Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator Brochure 
ICAM-1 
Intercellular Adhesion Molecule-1 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization  
IMAEs 
Immune-Mediated Adverse Events 
IFN 
Interferon 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
Inf.U 
Infectious Units 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 

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IV 
Intravenous 
L 
Liter 
LA 
Locally Advanced 
LLN 
Lower Limit of Normal 
LDH 
Lactate Dehydrogenase 
LFA-3 
Leukocyte Function-Associated Antigen 3 
LTFU 
Long Term Follow-up 
M 
Metastatic 
MCH 
Mean Corpuscular Hemoglobin 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Affairs 
mg 
Milligram 
mL 
Milliliter 
mmol 
Millimole 
MMR 
Mismatch repair 
MP 
Medical Product 
MRI 
Magnetic Resonance Imaging 
MSI 
Microsatellite instability 
MUC-1 
Mucin-1 
MVA 
Modified Vaccinia Ankara  
MVAC 
Methotrexate, Vinblastine, Doxorubicin, plus Cisplatin 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
NCI Common Terminology Criteria for Adverse Events 
NYHA 
New York Heart Association 
OS 
Overall Survival 
OR 
Objective Response 
ORR 
Objective Response Rate 
PBMC 
Peripheral Blood Mononuclear Cell 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PD-1 
Programmed Death 1 
PD-L1 
Programmed Death Ligand 1 

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PE 
Physical Examination 
PFS 
Progression-Free Survival 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PR 
Partial Response 
PSA 
Prostate Specific Antigen 
PT 
Prothrombin Time 
PV 
Pharmacovigilance 
RBC 
Red Blood Cells 
RDW 
Red Blood Cell Distribution Width 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SADR 
Serious Adverse Drug Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SC 
Subcutaneous 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SMT 
Safety Monitoring Team 
SOP 
Standard Operating Procedure 
T3 
Triiodothyronine 
T4 
Thyroxine 
TAA 
Tumor-Associated Antigen  
TCID50 
Tissue Culture Infectious Dose 
TCR 
T cell Receptor 
TEAE 
Treatment Emergent Adverse Event 
TIL 
Tumor-Infiltrating-Lymphocytes 
TNF 
Tumor Necrosis Factor 
Trial Vaccine 
MVA-BN-CV301 and FPV-CV301 
Trial Medication 
Atezolizumab 
Trial Product 
MVA-BN-CV301, FPV-CV301, and Atezolizumab 
TRICOMTM 
Triad of Costimulatory Molecules 
TSH 
Thyroid –Stimulating Hormone 

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TURBT 
Transurethral Resection of Bladder Tumor 
µL 
Microliter 
µm 
Micrometer 
UC 
Urothelial Cancer 
ULN 
Upper Limit of Normal 
US 
United States 
USA 
United States of America 
USPI 
United States Prescribing Information 
UTI 
Urinary Tract Infection 
WBC 
White Blood Cell 
WOCBP 
Women of child-bearing potential 

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1.4 Protocol Synopsis 
Title 
 A Phase 2, Multicenter, Single-Arm Trial of CV301 in Combination 
with PD-1/L1 Blockade in Patients with Locally Advanced or 
Metastatic Urothelial Bladder Cancer 
 
  
Clinical phase 
 Phase 2 
 
  
Sponsor 
 Bavarian Nordic A/S 
 
  
 
Number of sites 
  
Approximately 12 
 
 
  
Vaccination dose, 
schedule and 
administration route  
 
 
Prime with MVA-BN-CV301 (nominal titer 1.6 x 109 Inf.U) given 
subcutaneously (SC) on Day 1 and Day 22. One dose = four 0.5 mL 
injections. One injection = nominal titer 4 x 108 Inf.U in 0.5 mL. 
 
Boost with FPV-CV301 (nominal titer of 1 x 109 Inf.U in 0.5 mL, 
given SC every 21 days for 4 doses (on days 43, 64, 85, and 106), 
followed by boosts every 6 weeks until 6 months on trial (i.e., days 148 
and 190), then every 12 weeks until completion of 2 years. One dose = 
one 0.5 mL injection. 
 
Atezolizumab fixed dose of 1200 mg intravenous on Day 1 of each  
21-day cycle. No dose reduction permitted.  
 
  
Trial duration 
 
 
Approximately 104 weeks before starting the long term follow up. 
 
Trial Population 
 Patients with Locally Advanced or Metastatic Urothelial Cancer (UC) 
including bladder, ureter, renal pelvis and urethra. 
Cohort 1: Ineligible for cisplatin-containing chemotherapy (first-line 
treatment)  
Cohort 2: Previously treated with standard first-line cisplatin-based 
chemotherapy, PD-1/L1 Naïve (second-line treatment) 
 
  
Number of Subjects: 
 Approximately up to 68 
 
  
Primary objectives 
 Objective Response Rate (ORR; Complete Response [CR] + Partial 
Response [PR] Rate) as per Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1) 

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Secondary objectives  Progression-Free Survival (PFS)  
 
Overall Survival (OS) 
 
Duration of Response 
 
Safety of the treatment combination of CV301 with atezolizumab 
 
  
Exploratory 
objectives 
 Analysis of biopsy tissue for differences between pre- and post-
treatment samples correlation to patient survival e.g.: 
• 
T cell receptor (TCR) clonality 
• 
Tumor-Infiltrating-Lymphocytes (TILs) 
• 
Protein expression for e.g. Programmed Death Ligand 1 (PD-
L1) and other biomarkers 
• 
Gene expression profiling for molecular subtyping 
 
Analysis of tumor DNA for Tumor mutational burden; DNA damage 
response gene mutations, MSI status, MMR deficiency status 
 
Analysis of peripheral blood mononuclear cells (PBMCs) / serum for 
differences between pre- and post-treatment samples correlation to 
patient survival e.g.: 
• 
Antigen-specific immune responses to carcinoembryonic 
antigen (CEA) and mucin-1 (MUC-1) as well as to other 
tumor-associated antigens (TAAs) to assess antigen cascade 
• 
Immunophenotyping of immune cell subsets by flow cytometry 
• 
Soluble biomarkers (e.g. cytokines and classical tumor markers) 
• 
TCR clonality 
•           PD-1/L1 staining  
 
  
Primary endpoint 
 Proportion of subjects with a confirmed OR (CR+PR) as per 
investigator assessment according to RECIST 1.1.  
 
  

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Secondary endpoints 
 
Safety of the combined treatment as measured by: 
• 
Adverse Events (incidence, severity, and seriousness of treatment 
emergent adverse events [TEAEs]) 
• 
Laboratory Measures (summaries and shifts from baseline) 
• 
Vital Signs (summaries) 
 
OS defined as the time from start of treatment to the time of death from 
any cause. 
 
Duration of response defined as the time from the initial occurrence of 
documented complete response (CR) or partial response (PR) 
(whichever occurred first) until documented disease progression or 
death due to any cause on trial, whichever occurred first. 
 
PFS defined as the time from start of treatment to the first event of 
death or progressive disease (PD) per RECIST 1.1. 
 
Percentage of participants with OS and PFS at 6 (PFS only), 9 (PFS 
only), 12, 18 and 24 months. 
 
Immune-related Response Criteria assessment of response rate per 
iRECIST, delayed responses (pseudo-progressions), duration of 
response and PFS. 
 
 
 
Trial design 
 
Phase 2, Multicenter, Single-Arm, 2 Cohorts, Two-stage 
 
 
 
Inclusion criteria – 
ALL subjects 
 
1. The subject has read, signed and dated the Informed Consent Form 
(ICF), having been advised of the risks and benefits of the trial in a 
language understood by the subject.  The ICF must be signed prior 
to any protocol specific assessments. 
2. Age ≥ 18 years at date of ICF signature having the ability to 
comply with protocol. 
3. Histologically or cytologically documented locally advanced (T4b, 
any N M0; or any T, N 1−3 M0) or metastatic (M1, Stage IV; or 
metastatic recurrence after locoregional treatment) UC (including 
renal pelvis, ureters, urinary bladder, urethra).  
Note about the change in the definition of Locally Advanced 
from TNM v7 to the current v8, while all those cases were  
Stage IV in v7, with TNM v8 they are reclassified as Stage IIIA 
(T1-4a N1 M0) and Stage IIIB (T1-4a N2-3 M0). 
  
a. Patients with mixed histologies were required to have a 
dominant transitional cell pattern. 

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b. Locally advanced bladder cancer that was inoperable on the 
basis of involvement of the pelvic sidewall or adjacent 
viscera (clinical stage T4b) or bulky nodal metastasis 
(N2−N3). 
4. Life expectancy ≥ 12 weeks. 
5. Measurable disease, as defined by RECIST 1.1. Previously 
irradiated lesions cannot be counted as target lesions unless there 
has been demonstrated progression in the lesion since radiotherapy 
and no other lesions are available for selection as target lesions. 
6. Demonstrate adequate organ function as defined in Table 1. All 
screening labs should be performed within 14 days prior to the first 
trial product: 
Table 1: 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count 
(ANC) 
≥ 1,500 cells/μL 
Platelets 
≥ 100,000/μL 
Hemoglobin 
≥ 9.0 g/dL 
WBC 
> 2,500/μL 
Lymphocyte count 
≥ 300/μL 
Hepatic 
Total bilirubin 
≤ 1.5 x Upper Limit of Normal 
(ULN) OR 
Patients with known Gilbert 
disease who had serum bilirubin 
level ≤ 3 x ULN 
Aspartate aminotransferase 
(AST)/ Serum glutamic 
oxaloacetic transaminase 
(SGOT) and Alanine 
aminotransferase (ALT)/Serum 
glutamic-pyruvic transaminase 
(SGPT) 
≤ 2.5 x ULN with the following 
exceptions: 
≤ 5 x ULN for subjects with liver 
metastases OR 
Patients with documented liver 
or bone metastases: alkaline 
phosphatase ≤ 5 x ULN 
 
Serum Albumin 
≥ 2.5 g/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
 
 
 
≤ 1.5 x ULN unless subject is 
receiving anticoagulant therapy 
as long as PT or PTT is within 
therapeutic range of intended use 
of anticoagulants 
 

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Activated Partial 
Thromboplastin Time (aPTT) 
≤ 1.5 x ULN unless subject is 
receiving anticoagulant therapy 
as long as PT or PTT is within 
therapeutic range of intended use 
of anticoagulants 
7. For female patients of childbearing potential and male patients with 
partners of childbearing potential, agreement (by patient and/or 
partner) to use a highly effective form(s) of contraception (i.e., one 
that results in a low failure rate [< 1% per year] when used 
consistently and correctly).  Must be on acceptable method for at 
least 30 days prior to 1st dose of trial product and to continue its 
use for 5 months after the last dose of atezolizumab. 
8. Representative formalin-fixed paraffin-embedded (FFPE) tumor 
specimens in paraffin blocks (blocks preferred) or at least ten 4µm 
and one 20µm unstained slides, with an associated pathology 
report.  This specimen will be reviewed by a central reader but 
results of review will not be required prior to registration and 
treatment of the subject. 
a. Tumor tissue has to be of good quality based on total and 
viable tumor content. Fine-needle aspiration, brushing, cell 
pellet from pleural effusion, bone metastases, and lavage 
samples are not acceptable.  For core needle biopsy 
specimens, a result of ten 4µm and one 20µm slides of 
evaluable quality have to be submitted for evaluation. 
b. Patients who submitted transurethral resection of bladder 
tumor (TURBT) specimens are required to submit specimens 
containing muscle invasive component of the bladder tumor 
as verified by pathology review. If the TURBT specimens do 
not contain a muscle invasive component (i.e., T2 or 
greater), then specimens obtained at the time of 
cystectomy/nephroureterectomy or metastatic spread (i.e., 
sample from a metastatic lesion) are required. An archival 
specimen, if available, must also be submitted. 
c. Patients who do not have tissue specimens meeting 
eligibility requirements must undergo a biopsy sample 
collection during the screening period.  Acceptable samples 
include core needle biopsies for deep tumor tissue (resulting 
in ten 4µm and one 20µm slides of evaluable quality) or 
excisional, incisional, punch, or forceps biopsy samples for 
cutaneous, subcutaneous, or mucosal lesions. 
d. Patients having additional tissue samples from procedures 
performed at different times during the course of their 
urothelial carcinoma are requested (but not required) to also 
submit these samples for central testing. In situations where 
multiple specimens are received from different sites or at 

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different times, the highest score will be used for primary 
and secondary analyses. 
 
 
 
 
 
 
Inclusion for Cohort 1  9. Untreated with chemotherapy for metastatic disease 
10. Have at least one of the following: 
a. ECOG (Eastern Cooperative Oncology Group) performance 
status of 2. 
b. Glomerular filtration rate calculated as creatinine clearance 
(Cockroft-Gault formula) of ≥20 mL/min and less than 
60 mL/min 
c. Hearing loss or neuropathy of any cause Common 
Terminology Criteria for Adverse Events (CTCAE) 
Grade  ≥ 2. 
 
 
 
Inclusion for Cohort 2  11. Disease progression during or following treatment with at least one 
platinum-containing regimen (e.g., GC, MVAC, CarboGem, 
carboplatin-paclitaxel) for inoperable locally advanced or 
metastatic urothelial carcinoma or disease recurrence, as defined 
by: 
a. Regimen is defined as patients receiving at least one cycle of 
a platinum-containing regimen with response assessment. 
Patients who received one cycle of a platinum-containing 
regimen but discontinued due to toxicity are also eligible. 
b. Patients who received prior adjuvant/neoadjuvant 
chemotherapy and progressed within 12 months of treatment 
with a platinum-containing adjuvant/neoadjuvant regimen 
are considered as second-line patients. 
12. ECOG (Eastern Cooperative Oncology Group) performance status 
of < 2 
13. Calculated creatinine clearance (Cockroft-Gault formula) of 
≥20 mL/min 
 
 
 
Exclusion criteria for 
ALL subjects 
 
1. Any approved anti-cancer therapy, including chemotherapy, within 
3 weeks prior to initiation of trial product; the following exceptions 
are allowed: 
a. Palliative radiotherapy for bone metastases or non-target soft 
tissue lesions completed > 7 days prior to baseline imaging. 
b. Hormone-replacement therapy or oral contraceptives. 
2. Treatment with any other investigational agent or participation in 
another clinical trial with therapeutic intent within 28 days prior to 
Day 1 (first dose of trial product) given that all AEs related to prior 
treatment have resolved to baseline or Grade 1. 
3. Active central nervous system (CNS) metastases defined as 
computed tomography (CT) or magnetic resonance imaging (MRI) 

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evidence of progression and prior radiographic assessments or 
Leptomeningeal disease. 
Subjects that have had prior diagnosis need to have stable 
disease by having results or performing CT/MRI with 1 month 
prior to 1st dose of treatment. 
4. Uncontrolled tumor-related pain: 
a. Patients requiring pain medication must be on a stable 
regimen at trial entry. 
b. Symptomatic lesions amenable to palliative radiotherapy 
(e.g., bone metastases or metastases causing nerve 
impingement) should be treated prior to trial entry. 
c. Asymptomatic metastatic lesions whose further growth 
would likely cause functional deficits or intractable pain 
(e.g., epidural metastasis that is not currently associated with 
spinal cord compression) could be considered for loco-
regional therapy if appropriate prior to first dose of trial 
product. 
5. Uncontrolled pleural effusion, pericardial effusion, or ascites 
requiring recurrent drainage procedures (once monthly or more 
frequently) 
a. Patients with indwelling catheters (e.g., PleurX) are allowed. 
6. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca 
> 12 mg/dL or corrected serum calcium > ULN) or symptomatic 
hypercalcemia requiring continued use of bisphosphonate therapy 
or denosumab: 
a. Patients who are receiving bisphosphonate therapy or 
denosumab specifically to prevent skeletal events and who 
did not have a history of clinically significant hypercalcemia 
are eligible. 
b. Patients who are receiving denosumab prior to first dose of 
trial product have to be willing and eligible to receive a 
bisphosphonate instead while in the trial. 
7. Malignancies other than urothelial carcinoma within 3 years prior 
to Day 1, with the exception of those with a negligible risk of 
metastasis or death treated with expected curative outcome (such as 
adequately treated carcinoma in situ of the cervix, basal or 
squamous cell skin cancer, or ductal carcinoma in situ treated 
surgically with curative intent) or localized prostate cancer treated 
with curative intent and no intent for further treatment or incidental 
prostate cancer (T1/T2b, Gleason score ≤ 7 undergoing active 
surveillance and treatment naive). 
8. Pregnant and lactating women. 

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9. History of severe allergic, anaphylactic, or other hypersensitivity 
reactions to chimeric or humanized antibodies or fusion proteins, 
or aminoglycoside antibiotics or egg products, poxvirus-based 
vaccinations, or beef or bovine meat. 
10. Known hypersensitivity or allergy to biopharmaceuticals produced 
in Chinese hamster ovary cells or any component of the 
atezolizumab formulation. 
11. History of autoimmune disease, including but not limited to 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, 
vascular thrombosis associated with anti-phospholipid syndrome, 
granulomatosis with polyangiitis, Sjogren’s syndrome, Guillain-
Barre syndrome, multiple sclerosis, vasculitis, or 
glomerulonephritis. 
a. Patients with a history of autoimmune-related 
hypothyroidism on a stable, maintenance dose of thyroid 
replacement hormone with evidence of adequate control or 
response by TSH (per institution standards) and compliance 
with prescribed hormone replacement are eligible for this 
trial. 
b. Patients with controlled Type I diabetes mellitus on a stable 
dose of insulin and who are compliant with insulin regimen 
are eligible for this trial. 
c. Patients with history of vitiligo and controlled psoriasis are 
eligible for the trial. 
12. History of idiopathic pulmonary fibrosis, organizing pneumonia 
(e.g., bronchiolitis obliterans), drug-induced pneumonitis, 
idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan 
a. History of radiation pneumonitis in the radiation field 
(fibrosis) is permitted. 
13. Positive test for Human Immunodeficiency Virus (HIV). 
14. Patients with active hepatitis B virus (HBV; chronic or acute, 
defined as having a positive hepatitis B surface antigen [HBsAg] 
test at screening) or hepatitis C virus (HCV) 
a. Patients with past HBV infection or resolved HBV infection 
(defined as the presence of hepatitis B core antibody 
[HBcAb] and absence of HbsAg, negative polymerase chain 
reaction (PCR) for HBV) are eligible. HBV 
Deoxyribonucleic Acid (DNA) PCR must be obtained in 
these patients prior to Day 1. 
b. Patients positive for HCV antibody are eligible only if 
polymerase chain reaction is negative for HCV Ribonucleic 
Acid (RNA) prior to first dose of trial product. 

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15. Active tuberculosis. 
16. Signs or symptoms clinically significant of infection within 2 
weeks prior to Day 1. 
17. Received therapeutic oral or intravenous (IV) antibiotics within 1 
week prior to Day 1 
a. Patients receiving prophylactic antibiotics (e.g., for 
prevention of a urinary tract infection or to prevent chronic 
obstructive pulmonary disease exacerbation) are eligible. 
18. Significant cardiovascular disease, which includes but is not 
limited to New York Heart Association (NYHA) Heart Failure 
Class II or greater, myocardial infarction within the previous 3 
months, unstable arrhythmias, unstable angina. 
a. Patients with known coronary artery disease, congestive 
heart failure not meeting the above criteria, or left ventricular 
ejection fraction < 50% on a stable medical regimen that was 
optimized in the opinion of the treating physician, in 
consultation with a cardiologist if appropriate, are eligible. 
19. Major surgical procedure other than for diagnosis within 28 days 
prior to Day 1 or anticipation of need for a major surgical 
procedure during the course of the trial. 
20. Prior allogeneic stem cell or solid organ transplant. 
21. Administration of a live, attenuated vaccine within 4 weeks before 
Day 1 or anticipation that such a live attenuated vaccine would be 
required during the trial  
a. Influenza vaccination may be given during influenza season 
only (approximately October to March). Patients cannot 
receive live, attenuated influenza vaccine (e.g., FluMist®) 
within 4 weeks prior to Day 1 or at any time during the trial. 
22. Any other diseases, metabolic dysfunction, physical examination 
finding, or clinical laboratory finding giving reasonable suspicion 
of a disease or condition that contraindicated the use of an 
investigational drug or that could affect the interpretation of the 
results or render the patient at high risk from treatment 
complications. 
23. Prior treatment with CD137 agonists or immune checkpoint 
blockade therapies, including anti−CTLA-4, anti−PD-1, and 
anti−PD-L1 therapeutic antibodies 
24. Treatment with systemic immunostimulatory agents (including but 
not limited to IFNs, interleukin [IL]-2) within 6 weeks or five half-
lives of the drug, whichever was shorter, prior to Day 1. 

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25. Treatment with systemic corticosteroids or other systemic 
immunosuppressive medications (including but not limited to 
prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, and anti−tumor necrosis factor [anti-TNF] agents) 
within 2 weeks prior to Day 1, or anticipated requirement for 
systemic immunosuppressive medications during the trial 
a. Patients who receive acute, low-dose, systemic 
corticosteroid medications (e.g., a one-time dose of 
dexamethasone for nausea) or for prevention of 
hypersensitivity reactions to contrast agents may be enrolled 
in the trial.  
b. The use of inhaled, nasal, ophthalmic, intra-articular, 
auricular or topical corticosteroids, physiologic replacement 
doses of glucocorticoids (i.e., for adrenal insufficiency), and 
mineralocorticoids (e.g. fludrocortisone for adrenal 
insufficiency) is allowed. 
 
 
 
Statistical 
considerations 
 
Simon's two-stage design (Simon, 1989) will be used within each 
cohort. Due to the multiple testing involved in having two cohorts, the 
individual cohort alpha has been set to 0.025 (one-sided) to ensure a 
trial-wide type I error rate of α < 0.05.   
 
The design for the first cohort, platinum ineligible subjects, is based on 
a prior published ORR of 23% for atezolizumab monotherapy (Balar et 
al., 2017b). The null hypothesis that the true ORR is 0.23 will be tested 
against a one-sided alternative.  In the first stage, 14 subjects will be 
accrued. If there are 3 or fewer responses in these 14 subjects, the 
cohort will be stopped. Otherwise, 19 additional subjects will be 
accrued for a total of 33. The null hypothesis will be rejected if 13 or 
more responses are observed in 33 subjects. This design yields an 
actual 1-sided type I error rate of 0.0244 and power of 0.7027 when the 
true ORR is 0.43 for the combination. 
 
The design for the second cohort, platinum refractory subjects who are 
anti-PD-L1 naïve, is based on a prior published ORR of 15% for 
atezolizumab monotherapy (Rosenberg et al., 2016). The null 
hypothesis that the true ORR is 0.15 will be tested against a one-sided 
alternative.  In the first stage, 13 subjects will be accrued. If there are 2 
or fewer responses in these 13 subjects, the cohort will be stopped. 
Otherwise, 22 additional subjects will be accrued for a total of 35. The 
null hypothesis will be rejected if 10 or more responses are observed in 
35 subjects. This design yields an actual 1-sided type I error rate of 
0.0249 and power of 0.7092 when the true ORR is 0.33 for the 
combination. 
 

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Based on simulations with the two-stage, two-cohort design, the 
overall type-1 error rate will be approximately 4.7%, and the power for 
the study, indicating at least one of the two cohorts will be positive 
given the alternative hypotheses are true, is approximately 91%.  
 
 
 

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1.5 Trial Procedure Schedule 
Trial Procedure 
Screening 
Phase 
Day -28 to 
Day 1 
Week 
(3 wk interval +/- 4 days) 
Week 
(6 wk interval  
+/- 1 wk) 
Week 
(12 wk interval +/- 2 wks) 
Long Term 
FU 
1 
4 
7 
10 
13 
16 
22 
28 
40 
52 
64 
76 
88 
100 
EOT12 
3-month 
interval  
+/- 2 wks 
Day 
 
1 
22 
43 
64  
85 
106 
148 
190 
274 
358 
442 
526 
610 
694 
EOT 
 
 
 
Visit 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
Trial Procedures 
 
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam incl. 
vital signs2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted PE  
incl. vital signs2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
collected at all clinic visits (including atezolizumab dosing visits) 
 
Adverse Events4 
X 
collected at all clinic visits (including atezolizumab dosing visits) 
X4 
Survival Status and 
Auto-immune/ IM 
clinical manifestation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tumor Biopsy 
X5 
 
 
X6 
 
 
 
 
 
 
 
 
 
Radiology Assessments 
 
CT scan:  Thorax, 
Abdomen and Pelvis7 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 

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EOT = End of Treatment, PE = Physical Examination, AE = Adverse Event, SAE = Serious Adverse Event, AESI = Adverse Event of Special Interest, WOCBP = Women of Childbearing Potential 
1 ICF can be obtained prior to Screening visit  
2 Blood pressure and pulse rate should be obtained after the subject has been seated in an upright position for at least 5 minutes. 
3 Troponin I will only be measured if clinically indicated. 
4 The reporting period for non-serious AEs and unrelated SAEs/AESIs ends 30 days after last administration of the trial product. The reporting period for related SAEs/AESIs ends 100 days 
after last administration of the trial product. A phone follow-up will be performed 100 days after the last administration of trial product to collect this information and schedule a follow-up 
visit, if clinically indicated. 
5 Patients who do not have archived tissue specimens meeting eligibility requirements must undergo a biopsy sample collection during the screening period. Acceptable samples included core 
needle biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, punch, or forceps biopsy samples for cutaneous, subcutaneous, or mucosal lesions. 
Trial Procedure 
Screening 
Phase 
Day -28 to 
Day 1 
Week 
(3 wk interval +/- 4 days) 
Week 
(6 wk interval  
+/- 1 wk) 
Week 
(12 wk interval +/- 2 wks) 
Long Term 
FU 
1 
4 
7 
10 
13 
16 
22 
28 
40 
52 
64 
76 
88 
100 
EOT12 
3-month 
interval +/- 2 
wks 
Day 
 
1 
22 
43 
64  
85 
106 
148 
190 
274 
358 
442 
526 
610 
694 
EOT 
 
Visit 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
Laboratory Assessments 
 
Hematology8  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistry8  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV, HbsAg, HCV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INR, PT, aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid function test 
X 
X 
 
X 
 
X 
every 6 weeks 
 
Biomarker Analyses9 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Urinalysis  
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dosing 
 
Prime Vaccine:              
MVA-BN-CV30111 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Boost Vaccine:                
FPV-CV30111 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Atezolizumab    
 
X 
X 
X 
X 
X 
X 
every 3 weeks8,10 
 

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6 Optional at any of the following visits: Visit 3-6. 
7 If there is a medical reason, subject may have MRI instead of CT scan upon approval from BN. 
8 Hematology and Serum Chemistry will be performed prior to every atezolizumab infusion. Hematology will include hemoglobin, hematocrit, red blood cell count, total white blood cell count 
with differential, platelet count, mean cell volume, mean corpuscular hemoglobin, and red blood cell distribution width.  Serum chemistry will include: total protein, albumin, alkaline 
phosphatase, total bilirubin, ALT, AST, lactate dehydrogenase, creatinine, blood urea nitrogen, uric acid, glucose, calcium, phosphorus, bicarbonate, chloride, potassium, sodium, lipase and 
amylase.  
9 Sample collection (peripheral blood for PBMC, serum) must occur prior to vaccine dosing. Sample collection for Biomarker analyses should be repeated if subject comes off trial due to PD or 
AE or if the subject has an objective response. 
10 For WOCBP, a pregnancy test is required prior to every atezolizumab infusion. Urine or serum pregnancy test is acceptable at any given visit depending on investigator and/or patient 
preference. 
11 The trial subject must be kept under close observation at the clinical trial site for at least 30 minutes following vaccinations. 
12 EOT visit should take place within 28 days of withdrawal.

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2 Background Information and Scientific Rationale 
2.1 Introduction 
The estimated incidence of urothelial cancers -including bladder, ureter and renal pelvis- for 2017 
in the US is 146,650 cases. The mortality estimated for urinary system cancers is 32,190 deaths 
(Siegel et al., 2017). Approximately 5% of newly diagnosed bladder cancers present with 
metastatic disease and 30% with muscle-invasive bladder cancer. Roughly 50% of patients with 
muscle-invasive bladder cancer will develop distant metastasis (Milowsky et al., 2016). The 
median age of diagnosis of bladder cancer patients is 73 years, with more than 70% older than 65 
years (Miller et al., 2016).  
Before the Food and Drug Administration (FDA) approval of programmed death-1 (PD-1)/ 
programmed death ligand-1 (PD-L1) inhibitory antibodies in 2016 and 2017, chemotherapy was 
the only treatment available for locally advanced or metastatic urothelial bladder cancer. The 
most efficacious chemotherapy regimens are those containing cisplatin, which represents a 
challenge for frail and unfit patients. Low performance status, advanced age, compromised renal 
function and comorbidities limit the capability of these patients to cope with intensive platinum-
based regimens. A first step in selecting the proper treatment for UC patients is to identify to 
which category they belong, cisplatin eligible or ineligible. The category of cisplatin eligible 
patients is especially relevant for first-line treatment, since the administration of standard 
regimens such as DDMVAC [dose-dense methotrexate, vinblastine, doxorubicin and cisplatin] or 
cisplatin/gemcitabine is associated with a fraction of long-term survivors. However, the prognosis 
is dismal for patients with disease progression after first-line chemotherapy. The ORR was lower 
than 10% for all the single agents tested. No chemotherapy agent was ever approved by the FDA 
for second-line treatment and only vinflunine achieved the approval by the European Medicines 
Agency (EMA), based on a modest 2-month and non-statistically significant prolongation of OS 
in a randomized Phase 3 clinical trial (Balar et al., 2017a), (Bellmunt et al., 2009). A prognostic 
model was derived from the vinflunine pivotal trial database in which the most important 
prognostic factors were ECOG Performance status higher than 0, hemoglobin level less than 
10 g/dL and liver metastasis (Bellmunt et al., 2010). Time from prior chemotherapy was later 
identified as an additional independent prognostic factor and accordingly it was recommended as 
a stratifying factor in randomized clinical trials (Sonpavde et al., 2013). In a poster 
communication to the (ASCO) Annual Meeting 2014 (Sonpavde, 2014), twelve Phase 2 clinical 
trials studying single agents or combinations included 711 patients and the global median OS was 
6.8 months, 95% C.I. 6.2 to 7.3 months, with a range of 3.9 to 10.8 months. The median OS 
reported in the Phase 3 clinical trial that compared vinflunine versus investigator’s chemotherapy 
choice were 6.9 and 4.6 months respectively (Balar et al., 2017a), (Bellmunt et al., 2009).  
As of December 2017, the FDA has approved five PD-1/PD-L1 inhibitory antibodies for locally 
advanced (LA) or metastatic (M) UC. A summary of these drugs and labels is presented in the 
following table (Table 2). 

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Table 2:  Summary of Approved Anti- PD-1/PD-L1 Antibodies for Urothelial Cancer 
Drug 
Pembrolizumab Atezolizumab Nivolumab Avelumab Durvalumab 
Trade 
name 
Keytruda 
Tecentriq 
Opdivo 
Bavencio 
Imfinzi 
Regular 
approval 
LA/M 2nd -line 
Accelerated 
approval 
LA/M non-
eligible for 
cisplatin 
LA/M 2nd -
line 
LA/M non-
eligible for 
cisplatin 
LA/M 2nd 
-line 
LA/M 
2nd -line 
LA/M 2nd -
line 
LA = locally advanced, M = metastatic 
Atezolizumab was the first anti-PD-L1 approved by the FDA for urothelial cancer (UC). The 
IMvigor210 study is a multicenter, single-arm, two-cohort, Phase 2 trial, with inoperable locally 
advanced or metastatic UC whose disease had progressed after previous platinum-based 
chemotherapy. The study included 315 (cohort 1) and 310 (cohort 2) patients that were treated 
with intravenous atezolizumab 1200 mg, given every 3 weeks (Rosenberg et al., 2016). Co-
primary endpoints were the independent review facility-assessed ORR according to RECIST 1.1 
and the investigator-assessed ORR according to immune-modified RECIST, analyzed by 
intention to treat. Compared with a historical control overall response rate of 10%, treatment with 
atezolizumab resulted in a significantly improved RECIST 1.1 ORR 15% [11–20], p=0.0058. 
With a median follow-up of 11.7 months (95% CI 11.4–12.2), ongoing responses were recorded 
in 38 (84%) of 45 responders. Grade 3–4 treatment-related adverse events, of which fatigue was 
the most common occurred in 50 (16%) of 310 treated patients. Grade 3–4 immune-mediated 
adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased AST, 
increased ALT, rash, and dyspnea being the most common. The median OS was 11.4 months for 
the 100-patient cohort. The observed correlation between higher PD-L1 expression and longer 
OS supports the importance of adaptive immunity in driving benefit to immune checkpoint 
inhibitors. Moreover, the observed association between immune activation genes, immune 
checkpoint genes and PD-L1 expression in immune cells provides additional support to the 
concept that PD-L1 expression indicates adaptive immune regulation and a pre-existing but 
inhibited anticancer immune response.  
Patients participating in IMvigor210 could continue atezolizumab beyond progression at the 
investigator’s discretion until the loss of clinical benefit. In total, 137 patients continued 
atezolizumab out of 220 patients with progression. Five patients (3.6%) continuing atezolizumab 
after progression had subsequent responses compared with baseline measurements. None of those 
patients previously experienced a response (Necchi et al., 2017). These observations suggest that 
atezolizumab treatment beyond progression may result in nonclassical responses and durable 
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IMvigor211 is a Phase 3 study of atezolizumab in comparison with chemotherapy in people with 
advanced bladder cancer who were previously treated with a platinum-based chemotherapy. The 
study evaluated the efficacy and safety of TECENTRIQ compared with physician’s choice of 
chemotherapy (vinflunine, paclitaxel or docetaxel) administered every 3 weeks in 931 people 
with previously treated mUC, who had progressed during or following a platinum-based regimen. 
The primary efficacy endpoint was OS and key secondary endpoints include ORR, progression-
free survival, and DOR. The primary efficacy endpoint, OS, was to be tested in a successive 
fashion (hierarchical testing) in study populations defined by PD-L1 expression. Statistical 
significance needed to be achieved for the study populations in the following order: IC2/3 (≥5%), 
IC1/2/3 (≥1%), and ITT group. However, because such significance was not achieved for OS in 
the IC2/3 population, results could not be evaluated for statistical significance in the IC1/2/3 and 
ITT populations, and these analyses are considered descriptive in nature. The first population 
tested comprised people with the highest levels of PD-L1 expression (IC2/3), followed by those 
with any observable level of PD-L1 expression (IC1/2/3), and followed by the overall study 
population (intention-to-treat: ITT). Per the pre-specified hierarchical testing order, the IC2/3 
(≥5%) population was tested first, with an OS HR of 0.87 (95% CI: 0.63, 1.21; median OS 
(mOS) of 11.1 vs 10.6 months for atezolizumab and chemotherapy respectively); p=0.41. In the 
overall study population (ITT), people treated with atezolizumab achieved a mOS of 8.6 months 
(CI: 95%; 7.8, 9.6), compared with 8.0 months (CI: 95%; 7.2, 8.6) with chemotherapy (HR 0.85, 
95% CI 0.73–0.99). The OS rate at the 12 months landmark was 39.2% and 32.4% for 
atezolizumab and chemotherapy respectively. Overall response rates were like those previously 
reported in the Phase 2 IMvigor210 study and similar between the two study arms, 13.4% for the 
ITT population and 23% vs 21.6% for atezolizumab and chemotherapy respectively in the IC2/3 
population. The median duration of response (mDOR), for those receiving atezolizumab was 21.7 
months (95% CI: 13.0, 21.7) in the overall study population, compared with 7.4 months (95% CI: 
6.1, 10.3) for those receiving chemotherapy. At the time of data cutoff, 39 out of 62 (63%) of 
responders to treatment with atezolizumab continued to respond, compared with 13 out of 62 
(21%) of responders to chemotherapy (Powles et al., 2017). 
Results from a pembrolizumab Phase 3 trial in patients with advanced urothelial carcinoma that 
progresses after platinum-based chemotherapy have been published (Bellmunt et al., 2017). 
Pembrolizumab at a dose of 200 mg every 3 weeks was compared with investigator’s choice of 
chemotherapy with paclitaxel, docetaxel, or vinflunine. A total of 542 patients were enrolled and 
the co-primary endpoints were OS and PFS. The median OS in the total population was 10.3 
months (95% CI 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% 
CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P = 
0.002. The estimated progression-free survival rate at 12 months was 16.8% (95% CI, 12.3 to 
22.0) in the pembrolizumab group and 6.2% (95% CI, 3.3 to 10.2) in the chemotherapy group. 
The ORR was significantly higher (P = 0.001) in the pembrolizumab group (21.1%; 95% CI, 16.4 
to 26.5) than in the chemotherapy group (11.4%; 95% CI, 7.9 to 15.8). The estimated percentage 
of patients with duration of response of at least 12 months was 68% in the pembrolizumab group 
versus 35% in the chemotherapy group. Fewer treatment-related adverse events of any grade 
were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); 

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there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group 
than in the chemotherapy group (15.0% vs. 49.4%). 
Locally advanced or metastatic urothelial cancer cisplatin-ineligible patients for first-line 
treatment is a new approved FDA and EMA indication for both atezolizumab and 
pembrolizumab. Atezolizumab approval is based on IMvigor201 Phase 2 trial, a single-arm, 
multicentric study that included 119 patients evaluable (Balar et al., 2017b). The objective 
response rate was 23%, including 9% CR. Median DOR was not reached by the time of the 
publication, range 3.7 to 21+ months, with 70% of responses ongoing as of data cutoff. 
Responses were observed in all categories of cisplatin ineligibility: 25% in patients with impaired 
renal function, 25% in PS2 patients and 12% and 14% for patients with hearing loss and 
peripheral neuropathy respectively. The median OS was 15.9 months and 12-month landmark 
survival was 75%. AEs grade 3-4 were reported in 16% of patients, led to treatment 
discontinuation in 34% of patients and led to treatment withdrawal in 8%. IMAEs were reported 
in 12% of patients and grade 5 in 4 patients. Pembrolizumab approval is based on KEYNOTE-
052 Phase 2 trial, a single-arm, multicentric study that included 370 patients evaluable (Balar et 
al., 2017a). The objective response rate was 24%, including 5% CR. Median DOR was not 
reached by the time of the publication, with 78% of responses ongoing as of data cutoff. 
Responses were observed in all categories of cisplatin ineligibility: 27% in patients with impaired 
renal function, 26% in PS2 patients and 31% for patients with other reasons. AEs grade 3-4 were 
reported in 16% of patients, 5% leading to treatment discontinuation. In both trials, responses 
were observed across all categories of PD-L1 expression, with the clinically relevant fact that low 
or absent PD-L1 does not preclude response. 
2.2 Trial Rationale 
Several studies in mice have shown that poxvirus vector-based vaccines can generate activated T 
lymphocytes that infiltrate tumors and induce the expression of PD-L1 (Foy et al., 2016). 
Combinations of poxvirus vectored vaccines with inhibitors of PD-1 have shown synergistic 
effects in the laboratory (Foy et al., 2016). The available laboratory evidence constitutes the main 
rational for studying the combination of poxvirus-vectored vaccines with PD-1 and PD-L1 
inhibitors in humans. The acknowledgment that PD-1 and PD-L1 inhibitors are particularly active 
in patients with a pre-existing immune response has led to the hypothesis that tumors without an 
ongoing immune response (“cold tumors”) may require an immunotherapy capable of inducing 
tumor-specific T cells activation and trafficking to the tumor site. The use of effective vaccines is 
a rational solution to initiate a new immune response against those tumors lacking a pre-existing 
immune response. Cumulative evidence in different human tumors, including bladder cancer, 
lends support to the concept that the efficacy of PD-1 and PD-L1 inhibitors correlates with the 
mutational burden of cancer, and the probability of developing a spontaneous anticancer immune 
response depends on the immunogenicity of the neoantigens. On the other hand, the efficacy of 
PD-1 and PD-L1 inhibitors have clear clinical limitations, since almost half of the patients 
showing early benefit will experience progression during treatment, so enhancing the immune 
response by adding T cell clones capable to recognize cancer shared antigens could be a useful 

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therapeutic approach to improve the clinical results.  In summary, the different mechanisms of 
action of PD-1 and PD-L1 inhibitors and CV301 are considered potentially complementary and 
clinical trials exploring the potential of this combination are warranted. 
The expression of CEA in bladder cancer has been reported in the range of 41% to 90% (Jautzke 
and Altenaehr, 1982), (Allard et al., 1995), (Genega et al., 2000). The expression of MUC-1 has 
been reported in the range of 55% to 91% (Stojnev et al., 2014), (Fina et al., 2016), but in 100% 
the subgroup of metastatic lesions (Kaur et al., 2014). A summary can be found in Table 3. Since 
CV301 contains both CEA and MUC-1 human transgenes, it is expected that this active 
immunotherapy may benefit most patients with UC. 
Table 3:  Summary of CEA and MUC-1 Expression Levels in Urothelial Bladder Cancer 
Expression of CEA and MUC-1 on Urothelial Bladder Cancer 
TAA 
% Positive 
No. 
Pts. 
Stage 
Reference 
Comment 
CEA 
0 to 67 
12 
Unknown 
Hum Prot Atlas 
4 Antibodies 
  
57 
150 
Primary 
Jautzke 1982 
Increasing 
expression with 
grade and T stage 
  
90 
350 
Superficial 
Allard 1995 
  
  
41 & 63 
46 
High grade 
Genega 2000 
2 Antibodies 
  
MUC-1 
64 to 91 
12 
Unknown 
Hum Prot Atlas 
5 Antibodies 
  
62 
539 
Primary 
Stojnev 2014 
  
  
83 & 66 
323 
Prim. & Met. 
Kaur 2014 
  
  
55 
31 
CTC 
Fina 2016 
RNA by PCR 
2.3 MVA-BN-CV301 & FPV-CV301 Vaccine(s) 
2.3.1 Origin and Characteristics of MVA-BN Vector Backbone 
Vaccinia virus has been used for over 200 years as a vaccine for smallpox and has a well-
established safety profile. The virus actively replicates in human cells, resulting in the 
presentation of high levels of antigen to the immune system over a period of 1–2 weeks, 
substantially increasing the potential for immune stimulation. The immune response specific to 
vaccinia then eliminates the virus. As a result of its safety profile and ability to elicit both 
humoral and cell-mediated immunity in humans, the vaccinia virus was chosen as one of the 
vectors to deliver MUC-1, CEA, and Triad of Costimulatory Molecules (TRICOM) in previous 
National Cancer Institute (NCI)-sponsored trials. 
Despite the desirable features of poxviruses, replication-competent viruses like vaccinia should 
not be administered to severely immunocompromised subjects. To address this problem, an 

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attenuated vaccinia virus called Modified Vaccinia Ankara (MVA) was developed for high-risk 
individuals. MVA was generated by over 500 serial passages of a smallpox vaccine from Ankara, 
Turkey, in chicken embryo fibroblasts, resulting in over 15% loss of the vaccinia virus genome. 
MVA can infect mammalian cells and express transgenes, but it cannot produce infective viral 
particles.  
Bavarian Nordic (BN) has generated a proprietary isolate of MVA designated MVA-BN®. 
MVA-BN has been derived from the licensed MVA used in Europe by additional passages and 
limiting dilutions in Chicken Embryo Fibroblast cells under serum-free conditions and has been 
shown not to replicate in human cells and can be safely administered to severely immune 
compromised animals (Suter et al., 2009). Although MVA exhibits strongly reduced replication 
in mammalian cells, the block in viral replication resides at the level of virus assembly and egress 
(Sutter and Moss, 1992), (Carroll and Moss, 1997), resulting in efficient expression of viral as 
well as recombinant proteins. The ability to stably clone large amounts of foreign DNA into the 
MVA genome provides a versatile vaccine vector (Sutter and Staib, 2003)) and in addition to 
developing MVA-BN as a safer smallpox vaccine, BN has used this platform to develop various 
vaccines against infectious diseases and cancer (Harrer et al., 2005), (Cosma et al., 2003), (Di 
Nicola et al., 2003),(Di Nicola et al., 2004). 
2.3.2 Clinical Experience with MVA-BN and Recombinant MVA-based Vaccines 
MVA-BN Vector Platform 
MVA-BN is used by itself as a prophylactic vaccine for smallpox, currently approved in Europe 
and Canada (trade name IMVAMUNE® outside European Union [EU], trade name IMVANEX® 
in the EU). MVA-BN is also investigated as a vector for immunization against several infectious 
disease agents and tumor-associated antigens.  
To date, 22 clinical trials evaluating the safety and immunogenicity of MVA-BN have been 
completed and 2 clinical trials are ongoing. As of 12Feb2019, more than 8,800 subjects have 
been exposed to MVA-BN including risk groups with contraindications to conventional smallpox 
vaccines. Furthermore, BN has evaluated the safety and immunogenicity of MVA-BN-based 
recombinant vaccines (including MVA-BN-Filo) in healthy subjects, HIV infected individuals, 
populations with cancer and children.  
In total, for MVA-BN and MVA-BN-based recombinant vaccines, the exposure sums up to more 
than 13,300 subjects, having received more than 15,000 single doses of vaccine.   
For more details, refer to the current CV301 Investigator Brochure (IB).  

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2.3.3 Safety Overview of MVA-BN and Recombinant MVA-based Vaccines 
In all completed and ongoing clinical trials, vaccinations with MVA-BN have shown to be 
generally safe and well tolerated. No cases of death, assessed as being at least possibly related, 
have been reported for a subject in a clinical trial using MVA-BN. Results obtained from 
completed Phase 1 and 2 trials and ongoing trials with several recombinant MVA-BN based 
vaccines in healthy adults and children, HIV infected subjects and cancer subjects demonstrate a 
similar safety profile as MVA-BN alone.  
Additional information on the safety profile of MVA-BN and recombinant MVA-based vaccines 
is provided in the CV301 IB. 
 
Adverse Drug Reactions (ADRs) 
Looking only at the events that were reported by at least 1% of subjects, the majority of ADRs 
represented local vaccination site reactions as well as common systemic reactions typical for 
modern injectable vaccines and were classified as being mild to moderate in intensity and 
resolved completely without intervention within the first 7 days following vaccination. To date, 
no trends have been identified suggesting the occurrence of any particular unexpected adverse 
reactions or classes of adverse reactions following vaccinations with MVA-BN or its 
recombinants.  
Cardiac Signs and Symptoms 
Based on observations with replicating smallpox vaccines, particular attention has been placed on 
monitoring for cardiac signs and symptoms in all clinical trials using MVA-BN. Despite close 
cardiac monitoring, no confirmed event indicating a case of myo-/pericarditis has been observed 
in any completed MVA-BN trial. 
Serious Suspected Adverse Drug Reactions  
As of 12Feb2019, a total of 7 (7 out of 8,888 vaccinated subjects = 0.08%) serious suspected 
ADRs have been reported for MVA-BN smallpox vaccine in completed and ongoing trials. All of 
them have been thoroughly reviewed by BN and the trial specific Data and Safety Monitoring 
Board who concluded that the continued use of MVA-BN in a clinical setting presented no 
special risks to the subjects. No pattern regarding Serious Adverse Drug Reactions (SADRs) 
could be detected. For further details, please refer to the CV301 IB, Section 5.3.1. 
BN has evaluated the safety and immunogenicity of MVA-BN-based recombinant vaccines for 
several indications such as cancer, HIV and measles in more than 2,600 subjects including 
healthy and HIV infected populations. In recombinant MVA-BN vaccine trials, doses up to 
5 x 108 TCID50 were administered applying varying schedules of repeated vaccinations, e.g. a  
3-dose schedule was used for recombinant HIV vaccines and multiple vaccinations have also 
been performed in subjects receiving a recombinant therapeutic breast cancer vaccine 

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(MVA-BN-HER2). Results obtained from these Phase 1 and 2 trials demonstrate a similar safety 
profile and vector immunogenicity as compared to MVA-BN alone.  
Two of the recombinant vaccine trials allowed for a direct comparison with MVA-BN as an 
active control. These trials (HIV-POL-002 and HIV-NEF-004) were performed to evaluate 2 
different recombinant MVA-BN-based HIV vaccine candidates in HIV-infected subjects. In both 
trials, a total of 3 vaccinations with either the recombinant HIV vaccine or MVA-BN were 
performed according to a 0, 8 and 16-week regimen.  
In the ongoing Phase 1 lung trial (CV301-2015-201), during the Phase 1a dose escalation, a dose 
of 1.6 x 109 Inf.U was reached without observing any dose limiting toxicity (DLT). In Phase 1b 
of the lung trial (CV301-2015-201), a SAE of Pneumonitis with an immune-mediated etiology 
occurred in a 48-year-old female subject who was receiving a combination of MVA-BN-CV301 
and nivolumab for the treatment of NSCLC. The ADR was considered to be possibly related to 
MVA-BN-CV301 and probably related to nivolumab.  Following the onset of Pneumonitis, the 
subject experienced Vasculitis and Disseminated Intravascular Coagulation (DIC) which 
culminated in the fatal event of Multi-Organ Failure, all unrelated to treatment with MVA-BN-
CV301. A full review took place by BN and the designated trial SMT who concluded that the 
event met the criteria of a dose-limiting toxicity, but did not warrant changes to the risk-benefit 
assessment of MVA-BN-CV301 or to the conduct of the CV301-2015-201 clinical trial. 
Summary 
The safety profile of each of the trials with recombinant MVA-BN-based vaccines is comparable 
to the safety profile observed with MVA-BN trials as the occurrence of the ADRs is considered 
to be a reaction to the vector rather than the insert, based on previous experience with 
recombinant MVA-BN vaccine candidates.  
 
The safety of MVA-BN-CV301 in combination with checkpoint inhibitors is currently under 
evaluation in the ongoing Phase 1b portion of CV301-2015-201 trial. 
The overall frequency of immune mediated events under combination treatment of CV301 plus 
anti-PD1 appears to be in line with previously published experience for anti-PD1 alone (Brahmer 
et al., 2018). 
During the ongoing Phase 1b of CV301-2015-201, the more frequently occurring reactions such 
as local injection site reactions and general symptoms were in line with the experience during 
monotherapy in Phase 1, as well as with the overall backbone vector experience.  
2.4 Overview of Fowlpox virus (FPV) 
Fowlpox virus is a member of the genus Avipox, which is evolutionarily divergent from vaccinia 
virus and serologically non-cross-reactive (J. Taylor, 1988), (Beukema et al., 2006). Immune 

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responses to vaccinia do not block infection and immunization with fowlpox-based vectors. 
Hence vaccinia-primed or MVA-primed immune responses can be boosted with fowlpox vectors. 
In addition, fowlpox vectors do not replicate in human cells (only in avian cells) and are therefore 
much less of a safety risk than replication competent vaccinia-based vectors. Fowlpox vectors 
mediate a limited infection in human cells, with early viral and transgene expression, but late 
gene expression is blocked, and no infectious particles are produced. Thus, minimal viral surface 
antigen is made, and minimal neutralizing antibody immune responses are induced. This enables 
multiple boosting with the fowlpox-based vectors. 
FPV has been investigated and used in vaccine design for at least 2 decades. As with vaccinia 
virus, it offers the advantages of a large genome but provides an additional safety assurance by 
not being able to replicate in mammalian cells. Fowlpox virus-based vaccines (HIV, malaria, 
cancer) have been tested in both animals and humans. No safety concerns have been raised and 
the adverse events (AE) associated with the use of fowlpox vectors have been limited to mild 
injection site reactions (Beukema et al., 2006, Essajee and Kaufman, 2004, Webster et al., 2006). 
The recombinant FPV-CV301 vaccine is based on a fowlpox vector which is currently being 
evaluated as part of a prime-boost regimen in the treatment of metastatic castration resistant 
prostate cancer (PROSTVAC®). Priming with a recombinant vaccinia virus followed by several 
boosters of the corresponding recombinant fowlpox virus elicited maximum immune response to 
the expressed tumor antigen Prostate Specific Antigen (PSA), demonstrating the heterologous 
prime-boost concept using recombinant vaccinia and fowlpox virus based vaccines. 
2.4.1 Recombinant Poxvirus-based Vaccines Including Fowlpox-based Vaccines 
Fowlpox-based vaccines for the treatment of various cancers have been evaluated in human 
clinical trials sponsored by the NCI. Over 2,000 cancer subjects, most with metastatic disease, 
have been treated to date with these poxvirus-based vaccines (Kaufman et al., 2004). No 
significant safety issues were identified in these trials. 
Supportive clinical data were generated in the clinical development program of PROSTVAC in 
oncologic indications. For details describing the overall experience and safety profile of 
PROSTVAC, including the complete regimen, consisting of a vaccinia-based prime vaccination 
and repeated fowlpox-based boost vaccinations, using the same fowlpox vector as being used for 
FPV-CV301, please refer to the CV301 IB.  
2.5 Overview of the Predecessor Product PANVAC 
2.5.1 PANVAC-Early “First-Generation” Vaccine 
The Vaccinia virus became a first-line choice to develop a cancer immunotherapeutic approach 
due to its proven safety in different human trials, together with its robust potential to induce 
strong cell-mediated immune responses. Therefore, early attempts to generate effective oncologic 

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intervention strategies by NCI involved the PANVAC construct. It comprised a heterologous 
prime-boost vaccination regimen consisting of a replicating-competent Vaccinia-based delivery 
vector followed by a Fowlpox vector. Both vectors contained inserts corresponding to 3 genes 
encoding human immune costimulatory molecules (designated TRIad of COstimulatory 
Molecules, or TRICOMTM) including B7.1, intercellular adhesion molecule-1 [ICAM-1] and 
leukocyte function-associated antigen-3 [LFA-3]. In addition, these vectors also expressed the 
carcinoembryonic antigen (CEA) and MUC-1 transgenes. 
To date, PANVAC (consisting of PANVAC-V and PANVAC-F administered in a prime-boost 
regimen) has been administered to approximately 300 subjects in 7 clinical trials.  
For details please see the CV301 Investigator’s Brochure. 
2.5.1.1 Safety Overview of PANVAC 
During the initial stages of PANVAC’s development program, preclinical studies revealed no 
dose-limiting toxicity. As well, no major findings concerning biologically significant 
observations, body weight, hematology, and clinical chemistry were reported. Mainly, the non-
clinical treatment-related sequelae included mild, transient swelling and erythema at the 
subcutaneous injection site with dermal irritation, resolving within 2 to 4 weeks’ post-injection. 
Such profile, together with the data obtained from non-clinical immunogenicity and efficacy 
studies, provided a solid ground to proceed with the clinical development program towards 
human studies. 
More than 300 subjects have participated across 7 clinical trials, during which both, the vaccinia 
vector (PANVAC-V, inalimarev) and the fowlpox vector (PANVAC-F, falimarev) were 
investigated for the treatment of a variety of carcinomas including breast, ovarian, colorectal, 
pancreatic and bladder.  
Overall, the data accumulated so far have shown a reliable safety profile, demonstrating that 
PANVAC has been well-tolerated in all trials. The most frequent treatment-related AEs were 
injection site reactions, myalgia, fatigue, vomiting, nausea, and abdominal pain. The majority of 
vaccine-related AEs were Grade 1 or 2 in severity. Importantly, serious adverse events (SAEs) 
related to trial treatment, discontinuations due to AE, and deaths related to trial vaccine were rare 
(one death due to Grade 5 pulmonary infiltrate was assessed as possibly related to trial drug).  
Due to the fact that PANVAC constitutes an approach based on a replication-competent 
Vaccinia-based delivery vector, there are still some potential safety risks that have already been 
addressed during its development. Traditionally, similar constructs have been used as inoculation 
candidates against smallpox. Within this context, a series of cardiac AEs of inflammatory nature, 
such as myo/pericarditis with an incidence ranging from 1 in 175 to 1 in 216 vaccines has been 
reported (Zitzmann-Roth et al., 2015), (Elizaga et al., 2013),(Engler et al., 2015). As well, a 
recent prospective surveillance study concerning the use of replicating smallpox vaccines 

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revealed an increased risk for the development of cardiovascular symptoms such as chest pain 
(approx. 1 in 12 vaccines) and dyspnea (approx. 1 in 19 vaccines). The risk of myo/pericarditis 
associated with the replication-competent vaccinia virus has not been observed with MVA-BN or 
MVA-BN-based construct. Despite close cardiac monitoring throughout the clinical program, no 
confirmed event of a case of myo-/pericarditis has been observed and there is no evidence 
suggestive of any cardiac safety signal.  
Besides the considerations regarding the viral backbone, it is also relevant to bring into 
discussion the reliability exhibited by its different components. As previously stated, the 
PANVAC technological platform expresses inserts for 5 different transgenes, 3 of which 
constitute human costimulatory molecules (TRICOM) critical for T cell activation that have 
already shown to enhance T cell responsiveness in mice (Levy et al., 2004). In fact, the 
therapeutic use of costimulatory molecules has both an acceptable safety profile and 
immunogenic potential in the clinical and preclinical settings, further contributing in the 
development of different immunotherapeutic approaches. For instance, dendritic cells-derived 
exosomes expressing this set of molecules have already been tested in Phase 1 and 2 clinical 
trials with advanced malignancies (Pitt et al., 2016). Similarly, the use of costimulatory 
molecules was shown to enhance the immunogenic potential of the allogeneic tumor cell line 
RCC-26, improving its use as a vaccine in a Phase 1 trial in renal carcinoma subjects (Buchner et 
al., 2010). Importantly, the results obtained in these trials employing such set of molecules 
exhibited an acceptable safety profile. 
As well, aside from PANVAC, Bavarian Nordic also developed PROSTVAC, a prostate cancer-
specific immunotherapeutic candidate using a transgene for the PSA together with the TRICOM 
strategy. The data accumulated so far across different clinical trials revealed no major safety 
concerns. Thus, PROSTVAC seems to be well tolerated, with injection site reactions, fatigue and 
fever being the most frequently reported AEs. In addition, other events reported by > 10% of 
subjects included nausea, diarrhea, constipation, arthralgia and dizziness. It is important to point 
out that no signals of inflammatory cardiac reactions have been observed in the more than 1000 
subjects studied until now. In fact, the results obtained during a Phase 2 trial show that this 
immunotherapy had an acceptable safety profile, was well tolerated and associated with a 44% 
reduction in the death rate of the studied population, thus providing preliminary and stimulating 
evidence about the potential clinically meaningful benefits obtained after this therapeutic 
approach (Kantoff et al., 2010b). Such data support an acceptable safety profile compared with 
the placebo controlled arm that characterizes the TRICOM construct and strongly supports its use 
in targeted immunotherapies. 
2.6 CV301 Next Generation Product Following PANVAC 
Given the potential risks associated with the replicating capacity of the vaccinia-based 
PANVAC-V construct, the next generation cancer immunotherapeutic candidate, MVA-BN-
CV301, was generated by Bavarian Nordic. It constitutes a recombinant non-replicating 
poxvirus-based immunotherapy derived from the MVA-BN construct. The new CV301 strategy 

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encodes the same 5 transgenes expressed by the previous PANVAC vector: CEA, MUC-1, B7.1, 
ICAM-1 and LFA-3. However, these inserts encode each of the transgenes with amino acid 
sequences that are slightly different from the original vectors. In fact, MUC-1 has been modified 
with additional agonistic epitopes. Consequently, the CV301 construct is expected to promote an 
antigen-specific targeted immune response for tumors expressing these antigens. In addition, a 
change in biosafety level also characterizes the new CV301 construct. Thus, whereas vaccinia 
possesses a BSL-2, MVA has been categorized as BSL1 in Europe. As well, similarly to the 
earlier PANVAC concept, CV301 also encompasses a heterologous prime-boost regimen 
employing MVA-BN-CV301 priming doses followed by Fowlpox-based FPV-CV301 boosting 
doses, thus replacing the former PANVAC-V and PANVAC-F components. Given the 
similarities between the CV301 and PANVAC vectors, the clinical development program 
designed for CV301 will rely on the extensive nonclinical and clinical data currently available 
from PANVAC. 
In a first, still ongoing, BN-sponsored Phase 1 Trial of CV301 in Combination with Anti-PD-1 
Therapy versus Anti-PD-1 Therapy alone in Subjects with Non-Small Cell Lung Cancer (CV301-
2015-201), 12 subjects with various CEA/MUC-1 positive cancers were enrolled in the Phase 1a, 
6 male and 6 female subjects, aged between 39 and 77 years. Of these 12 subjects, 3 received 
MVA-BN-CV301 at the lowest dose level, nominal 4 x 108 Inf.U, 3 received the second dose 
level, nominal 8 x 108 Inf.U, and 6 received the highest dose level, nominal 1.6 x 109 Inf.U. 
Initial safety data from Phase 1 of this trial involving 12 subjects dosed in three different dose 
levels show that the most frequently occurring treatment-related AEs were temporary and self-
limiting, Grade 1 or 2 in severity and included injection site reactions (injection site erythema, 
pruritus, pain, induration and swelling) and general symptoms including fever/chills, flu-like 
symptoms, headache, fatigue/weakness, nausea/vomiting, myalgia and arthralgia. There was no 
occurrence of any of the pre-specified adverse events of special interest (immune-related events 
and cardiac events). There were no related SAEs. There were no dose limiting toxicities at all 
three investigated dose levels, so no maximal tolerated dose was identified. Based on this initial 
safety information, the selected dose level for the further course of the trial was nominal  
1.6 x 109Inf.U (i.e. 4 injections of 4 x 108 Inf.U in 0.5 mL) of MVA-BN-CV301. 
2.7 Trial Population 
The eligible population is based on the FDA approved indications of atezolizumab and the 
current standard of care; which includes: male and female subjects ≥18 years of age with locally 
advanced or metastatic UC, subjects will have mixed histologies that required having a dominant 
transitional cell pattern and locally advanced bladder cancer that is inoperable on the basis of 
involvement of the pelvic sidewall or adjacent viscera or bulky nodal metastasis. Metastatic 
subjects include Stage IV at first diagnosis and metastatic recurrences after locoregional 
treatments of earlier stages.   

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Bladder cancer subjects fit for first-line cisplatin are excluded because cisplatin-based 
combinations remain the standard treatment. The role of immunotherapy in this population is 
currently under clinical investigation but is not part of this clinical trial.  
Two different cohorts of subjects with locally advanced or metastatic urothelial cancer are 
eligible for this trial: subjects with disease progression after first-line cisplatin-base 
chemotherapy, or candidates to second-line treatment. Five different antibodies targeting PD-1 or 
PD-L1 are currently approved in this indication and collectively have shown a better therapeutic 
index than the historical results achieved with chemotherapy agents. The second cohort is 
comprised of candidates to first line treatment but cisplatin-ineligible due to some of the 
following conditions: ECOG PS2, renal function impairment, hearing loss or peripheral 
neuropathy.  
2.8 Risk/Benefit Assessment 
2.8.1 Potential Risks 
Considering that the novel MVA-BN-CV301 vector derives from the original MVA-BN 
construct and contains inserts already present in the PANVAC vector, its potential risks are based 
on the adverse reactions already reported for these two constructs. So far, within the MVA-BN 
clinical development program, more than 10,500 subjects have received at least one MVA-BN-
based construct dose in completed and ongoing clinical trials, giving rise to a substantial database 
concerning the administration of MVA-based recombinant vaccines in different populations. 
These include healthy vaccinia-naïve, healthy vaccinia-experienced, HIV-infected subjects, 
subjects with atopic dermatitis and subjects with previous hematopoietic stem cell 
transplantation. In addition, the vaccinia-based PANVAC vector has been administered to 
approximately 450 subjects in different cancer indications. The main adverse reactions associated 
with both MVA-BN and PANVAC inoculation involve the development of local reactions at the 
injection site, e.g. erythema, pain, swelling, induration and short-lived flu-like systemic effects, 
ranging from mild to moderate intensity and resolving completely within the first seven days 
after vaccination. Additional risks potentially associated with MVA-BN-CV301 include fatigue, 
abdominal pain, nausea, and vomiting. 
Despite the fact that the MVA-BN delivery vector constitutes a non-replicating, highly attenuated 
vaccinia viral strain, thorough cardiac monitoring protocols have been successfully implemented 
along the entire MVA-BN clinical development program. Similar safety measures were also 
carried out during clinical trials employing the replication-competent PANVAC and 
PROSTVAC-V constructs. No case of myocarditis, confirmed pericarditis, endocarditis or any 
other type of cardiac inflammatory disease (or related syndromes) has been reported to date for 
either of these products. However, several ischemic cardiac events and arrhythmias have been 
reported during PANVAC’s clinical development program, particularly in pancreatic cancer 
subjects. In this regard, it has been shown that pancreatic cancer can induce severe nutritional and 
metabolic dysfunctions, thus facilitating different types of arrhythmias. Therefore, it seems 

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neither PANVAC nor MVA-BN-based therapies might induce any inflammatory cardiac events, 
as opposed to the early generation replicating smallpox vaccines like Dryvax® and ACAM2000®. 
Furthermore, an additional series of potential risks associated with the current clinical trial 
protocol include those derived from blood and tissue sampling procedures. Blood draws may 
cause discomfort, bruising, light-headedness or fainting and rarely result in infection at the 
venipuncture site. Biopsy risk may include a small amount of bleeding, pain, swelling, bruising 
and possibly an infection.  As well, similar to other vaccines, there is a risk of an allergic reaction 
or an anaphylactic event. Consequently, in order to offer appropriate treatment and supervision in 
case of a severe allergic reaction and/or dyspnea, 30 minutes’ observation periods will be 
implemented by the trial site staff after each vaccination. Additionally, subjects with known 
severe allergies to eggs, egg products, or aminoglycoside antibiotics (for example ciprofloxacin, 
gentamicin or tobramycin) should be excluded from receiving MVA-BN-CV301. 
The risks associated with atezolizumab are described in the package insert and may be expected 
during the use of atezolizumab in this clinical trial. 
The risk derived from the combination of CV301 with the PD-1 inhibitors nivolumab and 
pembrolizumab is being studied in ‘A Phase 1/2 Trial of CV301 in Combination with Anti-PD-1 
Therapy Versus Anti-PD-1 Therapy Alone in Subjects with Non-Small Cell Lung Cancer’ 
(CV301-2015-201, NCT02840994). No safety signal has emerged so far from this ongoing trial. 
Although the specific combination of CV301 with atezolizumab is being studied for the first time 
in this clinical trial, the drug classes to which these compounds belong has been previously 
combined and no safety concern is expected. As an example of a poxvirus-vectored therapeutic 
cancer vaccine combined with an immune checkpoint inhibitor we refer to the Phase 1 trial that 
studied PROSTVAC with ipilimumab (Madan et al., 2012).  
2.8.2 Benefits 
The expected benefit from CV301 used as a single agent is unknown. A randomized Phase 2 
clinical trial comparing the use of the therapeutic cancer vaccine PANVAC in combination with 
docetaxel versus docetaxel alone showed a non-statistically significant trend in PFS in favor of 
the combination [7.9 months versus 3.9 months, HR=0.65, p=0.09] (Heery et al., 2015). 
Provenge® (Sipuleucel-T) is the first and only vaccine approved by the FDA and the clinical 
benefit observed in the pivotal clinical trial showed a unique pattern of OS prolongation without 
producing ORR nor PFS prolongation (Kantoff et al., 2010a). The recognition of this novel 
pattern of clinical benefit together with the observation of delayed responses triggered several 
initiatives to adopt new immunotherapy assessment criteria (Hoos et al., 2010). But results 
obtained with vaccines used as single agents may differ from results of vaccines used in 
combination.  
The expected clinical benefit from PD-1/PD-L1 inhibitors has a different pattern. A relatively 
small fraction of subjects achieves durable ORR and this fact translates usually into prolonged 

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OS. PFS is often reported as negative, statistically nonsignificant and with no advantage observed 
in medians, but the tails of the Kaplan-Meier curves tend to separate with long-term follow up, 
which seems consistent with a durable benefit experienced by a relatively small fraction of 
subjects. The results reported from the pembrolizumab Phase 3 clinical trial in second-line UC 
(Bellmunt et al., 2017) fit well with this pattern repeatedly reported across various PD-1/PD-L1 
inhibitors in multiple indications.  
The expected clinical benefit pattern from the combination of CV301 with PD-1/PD-L1 
inhibitors is uncertain at this moment. In this trial, ORR is selected as the key endpoint to capture 
the activity of the combination. Benefit is also expected in other endpoints, but OS and PFS are 
categorized as secondary endpoints. The safety information available on poxvirus-vectored 
vaccine justifies the expectation on CV301 contribution to therapeutic benefit without a 
substantial addition of toxicity. 
3 Objectives 
Refer to Trial Synopsis (Section 1.4). 
4 Trial Design 
4.1 Experimental Design 
This is a Phase 2, single-arm, multi-institutional clinical trial designed to study the combination 
of CV301 with atezolizumab in the first-line treatment of UC not eligible for cisplatin-containing 
chemotherapy (Cohort 1) and in the second-line treatment of UC previously treated with standard 
first-line cisplatin-based chemotherapy (Cohort 2).  The trial will be performed using an optimal 
two-stage design within each cohort (Simon, 1989). For the purpose of this trial, subjects are 
considered enrolled once they have received their first dose of trial product. 
Stage 1, Cohort 1: Enroll 14 subjects.  If objective response is not achieved in at least four 
subjects, the cohort will be stopped for futility.  If objective response is achieved in at least four 
subjects, the cohort will proceed to Stage 2. 
Stage 1, Cohort 2: Enroll 13 subjects.  If objective response is not achieved in at least three 
subjects, the cohort will be stopped for futility.  If objective response is achieved in at least three 
subjects, the cohort will proceed to Stage 2.  
Stage 2, Cohort 1: Enroll an additional 19 subjects, such that a total of 33 subjects are available 
for the primary endpoint analysis.   
Stage 2, Cohort 2: Enroll an additional 22 subjects, such that a total of 35 subjects are available 
for the primary endpoint analysis.   

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Further details of the two-stage design are in Section 9. 
4.2 Description of Trial Procedure 
This trial will be conducted according to the schedule found in Section 1.5 for ALL subjects.  
Visits should be scheduled within the intervals/visit windows given.  Protocol waivers or 
exemptions are not allowed, apart from immediate safety concerns.  Therefore, adherence to the 
design requirements including those specified in the Trial Procedure Schedule are essential and 
required for trial conduct.  
4.2.1 Screening Phase 
Patients identified as potential subjects in the trial will be provided with all the necessary 
information required to make an informed decision about their participation in the trial. At the 
conclusion of the informed consent process, subjects will be asked to provide written informed 
consent to participate in the trial by signing an ICF. This must be done before completing any 
protocol-specified procedures or evaluations (i.e., any procedures or evaluations not considered 
to be part of the subject’s normal care). After signing the ICF, subjects will be evaluated for entry 
criteria during the Screening period within 28 days before administration of trial drug. 
Subjects who fail the initial screening process may be re-screened up to 2 times. In the event of 
subject re-screening, the unique subject number assigned during the initial screening process 
should be used.  
After written, informed consent, screening assessment will be performed. All screening 
assessments must be performed within 28 days prior to the first trial product.  All screening labs 
should be performed within 14 days prior to the first trial product. 
The following task will be performed at the Screening Visit: 
• Demographics 
• Medical History 
• Physical Exam (PE) including vital signs* 
*Blood pressure and pulse rate should be obtained after the subject has been seated in 
an upright position for at least 5 minutes 
• ECOG 
• Electrocardiogram (ECG) 
• CT Scans of the thorax, abdomen and pelvis^ 
^If there is a medical reason, subject may have MRI instead of CT scan upon approval 
from BN. 
• Collection of concomitant medications 
• Collection of adverse events after signing of informed consent 
• Tumor biopsy**  

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**Subjects who do not have tissue specimens meeting eligibility requirements must 
undergo a biopsy sample collection during the screening period. Acceptable samples 
included core needle biopsies for deep tumor tissue (minimum three cores) or 
excisional, incisional, punch, or forceps biopsy samples for cutaneous, subcutaneous, 
or mucosal lesions). 
• Blood samples for: (see Section 8.2.7) 
o Hematology 
o Chemistry 
o Thyroid function test 
o INR, PT, aPTT 
o HIV, HBsAg, HCV 
o Biomarker analysis 
• Urine sample for routine urinalysis (see Section 8.2.7) 
• Pregnancy test – either serum or urine test (for women of child-bearing potential) 
Women and men of reproductive potential must consent to use of highly effective method of 
contraception at least 30 days prior to first dose of trial product and continue for 5 months after 
the last dose of atezolizumab (see Appendix 1, Section 17.1) and the method(s) used by each 
subject must be documented. This list does not apply to subjects with same sex partners or for 
subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long term 
and persistent basis, when this is their preferred and usual lifestyle. 
4.2.2 Active Trial Phase 
After successfully passing the screening evaluations, the eligible subjects will enter the active 
trial phase starting with Visit 1-14.   
4.2.2.1 Randomization 
Not applicable. This is a single-arm, non-randomized clinical trial. 
4.2.2.2 Visit Description 
The following tasks will be performed at Visits 1-14. 
• Targeted PE including vital signs* 
*Blood pressure and pulse rate should be obtained after the subject has been seated in 
an upright position for at least 5 minutes 
• ECOG 
• Pregnancy test – either serum or urine test (for women of child-bearing potential) 
• Review of concomitant medications 
• Recording of AEs 
• Blood samples for: (see Section 8.2.7) 

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o Hematology 
o Chemistry 
In addition, at Visit 1: 
• Thyroid function test 
• First prime vaccination of MVA-BN-CV301** and atezolizumab infusion. 
** The trial subject must be kept under close observation at the clinical trial site for at 
least 30 minutes following vaccinations 
In addition, at Visits 2, 4, and Visits 6-14: 
• Urine sample for routine urinalysis (see Section 8.2.7) 
In addition, at Visit 3, 4, 5, or 6: 
• Tumor biopsy# 
#Note: Biopsy is optional and can be performed at Visit 3, 4, 5, or 6. 
In addition, at Visits 3, 5 and every 6 weeks through to Visit 14: 
• Thyroid function test 
In addition, at Visits 4 and Visits 7-14: 
• CT scan of the thorax, abdomen and pelvis^ 
^If there is a medical reason, subject may have MRI instead of CT scan upon 
approval from BN. 
In addition, at Visits 2, 4, 7 and 10: 
• Blood sample for biomarker analysis  
In addition, at Visit 2: 
• Second prime vaccination of MVA-BN-CV301 and atezolizumab infusion. 
** The trial subject must be kept under close observation at the clinical trial site for at 
least 30 minutes following vaccinations 
In addition, at Visits 3-14: 
• Boost vaccinations of FPV-CV301 and atezolizumab infusion 
** The trial subject must be kept under close observation at the clinical trial site for at 
least 30 minutes following vaccinations 
Atezolizumab dosing visits: Every 3 weeks after Visit 6 through Visit 14 

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• Blood samples for: (see Section 8.2.7) 
o Hematology 
o Chemistry 
• Pregnancy test – either serum or urine test (for women of child-bearing potential) 
• Review of prior/concomitant medications 
• Recording of AEs 
• Atezolizumab infusion 
4.2.3 Long Term Follow-up Period 
During the Long-Term follow-up (LTFU) period, subjects will be followed by phone contact at 
quarterly intervals for survival status assessment and potential autoimmune or immune-mediated 
clinical manifestations. The FU period may be extended up to 2 years. 
4.2.4 Unscheduled Visits 
Additional visits to the clinic may be necessary between scheduled visits based on a subject’s 
health status and the investigator’s clinical opinion. Unscheduled visits may be performed to 
repeat laboratory testing, ECG or physical exams due to a new development. Examinations 
performed at unscheduled visits will be documented in the source documents as well as in the 
respective Electronic Case Report Form (eCRF) sections for unscheduled visits. 
4.2.5 Premature Discontinuation 
4.2.5.1 Discontinuation from Treatment 
Subjects may discontinue from treatment at any time. The decision to discontinue trial product 
may be made by the sponsor, investigator or the subject due to, but not limited to, the following: 
• 
Subject’s request to discontinue (withdrawal of consent to participate). 
• 
Subject’s unwillingness or inability to comply with trial requirements. 
• 
Occurrence of an AE or SAE attributable to a particular agent may result in 
discontinuation of that agent. The other agent can be continued until other stopping 
criteria are met. 
• 
Progressive disease (PD) according to RECIST 1.1 (Section 17.4). Note: The only 
exception to this reason for treatment discontinuation is when the investigator feels 
the RECIST PD may correspond to a pseudoprogression. In this case the investigator 
is allowed to continue the treatment and schedule a new tumor evaluation as per 
iRECIST guidance (Seymour et al., 2017). The clinical conditions suggesting 
pseudoprogression include symptoms improvement or stabilization, absence of 
ECOG PS deterioration and absence of unequivocal laboratory parameters or signs of 

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progression. A 3.6% of ORR have been reported with atezolizumab treatment beyond 
progression in a post hoc analysis of IMvigor210 Cohort 2 (Necchi et al., 2017).  
• 
Clinical deterioration without radiographic progression. 
• 
Initiation of any other anti-cancer treatment not allowed by the protocol. 
• 
Any reason that, in the opinion of the investigator, precludes the subject from 
receiving further trial product. 
• 
The trial is stopped or suspended on medical, scientific, or other grounds. 
The following procedures must be followed for subjects who discontinue prematurely from trial 
product: 
• 
If the subject is unable or unwilling to attend all planned visits, every attempt should 
be made to perform at least a final concluding safety visit, i.e., End of Treatment 
(EOT) Visit 14/Week 100 within 28 days of withdrawal. 
▪ If progression is observed on the CT scan scheduled per protocol or decided ahead 
of protocol-schedule for clinical reasons, CT scan does not have to be repeated. 
• 
Subjects who are discontinued from treatment in the absence of disease progression 
(e.g., subjects removed for unacceptable toxicity or subject/investigator discretion) 
should undergo repeat imaging and tumor response assessments until disease 
progression is documented. Radiological assessment should be continually 
performed as per schedule. It is recommended that subsequent therapy not be 
instituted until disease progression is documented. 
If the subject is unwilling or unable to come to the clinic for a final EOT assessment, all efforts 
by the investigator and/or site staff to contact the subject need to be fully documented in the 
Investigator Site File and the End of Treatment eCRF page, as instructed. Subjects that are 
withdrawn from treatment will enter the LTFU period. 
4.2.5.2 Discontinuation from Long Term Follow-up 
All subjects will be followed until death, via telephone contacts at 3 month intervals, to evaluate 
OS unless the trial is suspended or discontinued.  The length of the LTFU is planned to be 2 
years, unless all subjects achieve their OS endpoint prior to the end of the 2-year period.  If a 
subject chooses to withdraw from trial survival follow-up, this request must be documented in the 
source documentation and signed by the investigator. If the subject withdraws from participation 
in long term telephone follow-up, the trial staff may use a public information source (such as 
county records) to obtain information about survival status only.   
4.3 Trial Duration 
• 
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• 
Treatment Phase – approximately 100 weeks 
• 
Long Term Follow-up – Until all subjects achieve the OS endpoint, or a maximum 
time of up to 2 years 
The total duration of the trial for each subject is up to 4 years. 
4.4 Safety Monitoring Team 
The Safety Monitoring Team (SMT) is a board that oversees the safety of subjects participating 
in the trial. The members of the SMT consist of Trial Investigators, the medical monitor (BN), 
and the Director Pharmacovigilance (PV; BN). The primary responsibility of the SMT is to 
review and evaluate the accumulated trial data per the SMT Charter. 
If an event occurs which fulfills the trial halting rules (see Section 4.6 for further details), the 
SMT will review the event in a timely manner and agree on a recommendation to halt, resume, or 
terminate the trial participation of the affected subject(s), and/or request advice from the DSMB 
on continuation, modification, or termination of the trial.   
A separate charter describes in detail relevant operational procedures, communication pathways, 
roles, and responsibilities of the SMT in the trial.  
4.5 Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) is an independent board of experts responsible 
for reviewing clinical trial data on an ongoing basis to ensure the safety of trial subjects and 
validity and integrity of the trial data. The members of the DSMB are independent, i.e., not 
involved as investigators on any BN trial and have no direct or indirect financial interests in BN. 
The primary responsibility of the DSMB is to review periodically and to evaluate the 
accumulated trial data for participant safety and for the validity and integrity of the data and to 
make recommendations to BN concerning the continuation, modification, or termination of the 
trial.  The DSMB considers trial specific data, relevant background knowledge about the disease 
and trial population, and safety data from other trials studying CV301(monotherapy or in 
combination with immune checkpoint inhibitors) in the reviews. 
A separate charter describes in detail relevant operational procedures, communication pathways, 
roles, and responsibilities of the DSMB in the trial. 
4.6 Trial Halting Rules 
4.6.1 Safety Halting Rules 
A temporary halting or termination for the trial as a whole can be decided by the SMT and/or 
DSMB following the occurrence of: 

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• 
Unexpected (i.e., not listed in the current IB) Grade 3 or higher systemic reaction or 
lab toxicity (using NCI CTCAE version 5) with an at least reasonable possibility of a 
causal relationship to the administration of BN-CV301 vaccine (i.e., the relationship 
to vaccine cannot be ruled out).  
• 
Any unexpected SAE with a consequence of death 
Unexpected severity or higher than expected frequency of immune-mediated adverse events 
described in atezolizumab full prescription information insert and/or other scientifically relevant 
guidelines such as ASCO Practice Guideline on the management of immune-related adverse 
events in patients treated with immune checkpoint inhibitor therapy (Brahmer et al., 2018).  
These parameters are not all-inclusive. Other AEs could occur that would trigger a SMT review. 
If an event fulfilling the trial halting criteria reaches the investigator’s attention, the investigator 
has the responsibility to alert the PV Department immediately (within 24 hours) and provide a 
comprehensive documentation of the event. 
4.6.2 Efficacy Halting Rules 
Individual cohorts may be stopped for futility based on the planned two-stage trial design within 
each cohort. The two-stage design allows for an interim analysis of the primary efficacy 
endpoint, which allows the cohort to stop early if the required number of objective responses is 
not achieved within a cohort. Details of the efficacy endpoints and futility stopping rules are in 
Section 9. 
5 Selection of Subjects 
Each investigator will maintain a log of subjects screened for the trial. Included in the log must 
be documentation of the reason(s) a particular subject failed the screening process. 
5.1 Recruitment Procedure 
Subjects will be actively recruited. Recruitment strategies, including Institutional Review Board 
(IRB) approved advertisements, will be evaluated by the Sponsor. 
Recruitment will be performed in two stages within each cohort.  Once Stage 1 is fully enrolled 
in a cohort, an interim analysis of the primary efficacy endpoint will be performed to determine 
whether or not the cohort will continue on to Stage 2.  Details of the enrollment of subjects for 
each stage and sample size are found in the Protocol Summary (Section 1.4). 
Patients identified as potential subjects in the trial will be provided with all of the necessary 
information required to make an informed decision about their participation in the trial. 

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5.2 Inclusion Criteria 
A subject will be eligible for inclusion in this trial only if ALL of the inclusion criteria apply.  
Refer to Trial Synopsis (Section 1.4). 
5.3 Exclusion Criteria 
A subject will not be eligible for inclusion in this trial if ANY of the exclusion criteria apply.  
Refer to Trial Synopsis (Section 1.4). 
6 Investigational Medicinal Product 
6.1 MVA-BN-CV301 
MVA-BN-CV301 vaccine is a frozen suspension for injection, highly attenuated, live 
recombinant virus based on the viral vector MVA-BN. It is administered as SC application.  
One MVA-BN-CV301 vial has a nominal virus titer of 4 x 108 Inf.U in 0.5 mL of the drug 
product. 
For further details on MVA-BN-CV301 vaccine, see current version of the CV301 IB. 
6.2 FPV-CV301 
FPV-CV301 is a frozen suspension for injection, highly attenuated, live recombinant virus. It is 
administered as SC application. 
One FPV-CV301 vial has a nominal virus titer of 1 x 109 Inf.U in 0.5 mL of the drug product.  
For further details on FPV-CV301 vaccine, see current version of the CV301 IB. 
6.3 Atezolizumab (Tecentriq ®) 
Tecentriq ® (atezolizumab) is a commercially available fully humanized, engineered monoclonal 
antibody of IgG1 isotype against the protein PD-L1 approved for the treatment of locally 
advanced or metastatic urothelial carcinoma that has progressed after platinum-containing 
chemotherapy. 
The recommended dose of atezolizumab is 1200 mg administered as an intravenous infusion over 
60 mins every 3 weeks. If the first infusion is tolerated, all subsequent infusions may be delivered 
over 30 minutes. Do not administer as an intravenous push or bolus. 
For more details, refer to the prescribing information at 
https://www.gene.com/download/pdf/tecentriq_prescribing.pdf . 

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A hard copy of the atezolizumab prescribing information will be provided to the site in the trial 
reference manual.  
Also refer to the ASCO Practice Guideline on the management of immune-related adverse events 
in subjects treated with immune checkpoint inhibitor therapy (Brahmer et al., 2018). 
6.4 Production, Packaging and Labeling 
Both the MVA-BN-CV301 and FPV-CV301 bulk drug substances are produced at Bavarian 
Nordic A/S, Denmark.  
The final drug product is filled, formulated and labeled at Bavarian Nordic A/S, Denmark. 
The packages and vials of MVA-BN-CV301 and FPV-CV301 vaccines are labeled with US 
investigational new drug (IND) labels. 
Atezolizumab is provided by Roche as “naked” vials, then shipped to the contracted US depot for 
packaging and labeling. 
The packages and vials of atezolizumab are labeled with US required label text. 
6.5 Shipment, Storage and Handling 
Only subjects enrolled in the trial may receive trial product. 
Supplies of trial product (MVA-BN-CV301, FPV-CV301, and atezolizumab) will be shipped 
temperature controlled and monitored, to the clinical trial site from a central US depot. Once 
arriving at the site, the package should immediately be handed over to personnel in charge of trial 
product preparation (e.g., the pharmacist). Site personnel are responsible for proper storage of the 
trial product. Upon receipt, all trial product must be stored in a secure environmentally controlled 
and monitored area in accordance with the labelled storage conditions with access limited to the 
investigator and authorized site staff. 
Both the MVA-BN-CV301 and the FPV-CV301 vaccines must be shipped to the site and stored 
at a temperature of -20°C ± 5°C or -80°C ± 10°C avoiding direct light. A vial must not be re-
frozen once it has been thawed. 
Atezolizumab must be shipped to the site and stored at a temperature of 2°C - 8°C avoiding direct 
light.  
Additional details on the shipment, storage, handling and temperature deviations of the MVA-
BN-CV301, FPV-CV301 and atezolizumab can be found in a separate pharmacy manual supplied 
to each clinical trial site. 

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6.6 Preparation, Administration and Dosage 
Detailed trial-specific instructions on the preparation and administration of MVA-BN-CV301 
(prime vaccine), FPV-CV301 (boost vaccine) and atezolizumab are provided in a separate 
pharmacy manual supplied to each clinical trial site.  
6.7 Accountability and Disposal 
Used (if allowed by institutional policy) and unused vials of all trial product need to be retained 
in a place with limited access until appropriate drug accountability has been performed. Drug 
accountability must be documented whenever the trial product is either prepared or administered.   
BN will provide a Drug Accountability Log for recording receipt, dispensation, and destruction 
of trial product (see Pharmacy Manual). Alternative systems used to track drug accountability are 
acceptable for use in the trial provided the aforementioned items are adequately captured and 
records are available for review during scheduled monitoring visits to the site.  
After drug accountability has been performed, used and unused vials should either be returned to 
BN, to the designated drug depot, or discarded according to local regulations. 
Destruction or return of trial product must be agreed upon with BN and appropriately 
documented. Documentation should be reviewed and signed off by the pharmacist and Clinical 
Research Associate (CRA) assigned to monitor the site.  
Sites are responsible for the proper destruction and disposal of used needles and syringes and this 
should be done according to local regulations. If local disposal is not possible, used clinical 
supplies may be returned to the Sponsor or to the designated drug depot after prior consultation 
with BN. 
7 Blood and Tissue Collection for Correlative Biomarker Studies for 
Exploratory Analyses 
A total of up to 390 mL of whole blood, archived tumor tissue, and one or two tumor biopsies 
(optionally) will be collected from each subject during the course of the trial to assess the 
vaccine’s immunogenicity and to allow the identification of predictive or pharmacodynamic 
biomarkers.  
Biomarker testing will be performed at BN and/or selected CRO. Standard Operating Procedures 
(SOPs) effective at the time of testing will be followed. 
The exact procedures for collection, preparation and storage of specimens for exploratory 
analyses will be described in a separate study-specific instruction provided to investigators and 

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clinical trial site personnel during trial start-up. Site personnel will receive technical training on 
all procedures during the investigator meeting and/or the site initiation visit. 
7.1 Collection of Blood Samples  
PBMC and serum (for biomarker analyses) will be collected from all enrolled subjects as 
described in the Trial Procedure Schedule (Section 1.5). Sample collection must occur prior to 
vaccine dosing. 
7.2 Collection of Tumor Tissue 
Archived or fresh tumor tissue will be collected as described in the trial procedure schedule. 
Subjects must have, prior to trial product administration, unstained tissue slides (10 x 4µm and 
1 x 20µm sections; or a tissue block from which those slides can be cut) from a prior biopsy or 
surgical resection for submission for research purposes. Archival tumor biopsies obtained from 
the invasive primary cancer or metastatic disease performed prior to first dose are acceptable. 
If no archived tumor material meeting the specified criteria is available, a fresh biopsy at 
Screening is mandatory. 
Tumor biopsies at Visit 3, 4, 5, or 6 are optional as described in the Trial Procedure Schedule 
(Section 1.5). A refusal of the biopsy at Visit 3-6 has no impact on the subject’s trial participation 
and treatment. For responders, it is recommended to perform the biopsy at the time of optimal 
response but before CR is reached. For subjects with progression, it is recommended to perform 
the biopsy as soon as progression is confirmed and before starting the next treatment. 
For biopsies, the subjects will consent at the time of the procedure. Subjects imaging and clinical 
status will be reviewed with interventional radiology. Only if the subject is determined to be at 
low risk for significant complications from biopsy by interventional radiology will the subject be 
given the option to proceed with biopsy. The subject will be informed that there is no individual 
benefit from the biopsy and no results will be communicated to the subject. If the subject refuses 
the biopsy at that time, the refusal will be documented in the medical record and in the research 
record.  
7.3 Exploratory Analyses 
Exploratory analyses will be performed as outlined in the trial synopsis (Section 1.4) and will 
comprise e.g. Immunogenicity testing of PBMC and tumor tissue (e.g. T cell receptor clonality, 
TILs or antigen specific immune responses to CEA and MUC-1 as well as to other TAAs).  
Serum will be analyzed for soluble biomarkers (e.g. cytokines and classical tumor markers). 

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Tumor cells will be evaluated for gene or protein expression (e.g. PD-L1 or classical tumor 
markers). 
Tumor DNA may be analyzed for mutational burden; DNA damage response gene mutations, 
MSI status, MMR deficiency status 
7.4 Future Use of Lab Specimen 
Specimens remaining after completion of all immunogenicity testing for the trial will be stored 
for future analysis supporting the licensure path of CV301. Subjects will be asked to consent to 
storage/future use of their samples and will be informed about data protection measures. 
Specimens will be stored in Bavarian Nordic’s secured laboratory area or at an external storage 
facility in a coded, pseudonymized manner to ensure data protection. 
8 Safety  
For the purposes of this trial, “trial vaccine” is defined as CV301 and “trial medication” is 
defined as atezolizumab. “Trial product” refers to both, CV301 and atezolizumab collectively. 
Safety will be monitored by performing physical examinations including vital signs, routine 
laboratory measurements, as well as by evaluating AEs. 
Investigators are responsible for monitoring the safety of subjects who have entered this trial and 
for assuring appropriate medical care is provided. In addition, investigators are responsible for 
alerting BN or designee to any event that seems unusual, even if the event may be considered an 
unanticipated benefit to the subject, and for reporting the event on the appropriate AE eCRF or 
safety report form.  
Investigators are responsible for providing subjects who experience AEs, especially SAEs that 
cause subjects to discontinue participation in the trial, with appropriate medical care. Frequency 
of FU of any particular AE is left to the discretion of the investigator. Duration of FU and 
requirement for immediate SAE reporting (within 24 hours of becoming aware of the event) are 
described in Section 8.2.5 and Section 8.3.1. 
 
 

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8.1 Definitions 
8.1.1 Medical History 
Diseases, treatments and surgical interventions present before and up to signing of ICF will be 
considered medical history.  Medical history will be collected and documented in the Medical 
History eCRF at the screening visit.  Special attention should be given to any history of prior 
allergic reactions, especially to vaccines.   
8.1.2 Adverse Events 
AEs are defined as any untoward (undesirable) occurrence of a medical event in a clinical trial 
subject temporally associated with the administration of an IMP or a medical product (MP) which 
does not necessarily have a causal relationship with this IMP/MP.  The investigator and their 
designees are responsible for detecting, documenting and reporting events that meet the definition 
of an AE.   
Collection of non-serious AEs begins at the time the subject signs informed consent and 
continues for 30 days following administration of the last dose of trial product. 
Abnormal laboratory values assessed as being clinically significant by the investigator are to be 
documented as AEs. In addition, abnormal laboratory values fulfilling the Grade 3 or Grade 4 
criterion according to the toxicity scale (Appendix 2; Section 17.2) are to be documented as AE 
in the CRF, regardless of whether they are considered clinically relevant or not.  Toxicity grade 
and seriousness of an AE will be assessed separately, i.e., a Grade 3 or Grade 4 AE will not 
automatically be regarded as serious. 
Clinically significant findings from the treatment period physical examinations will be recorded 
as AE. 
8.1.3 Adverse Event of Special Interest (AESI) 
Immune Mediated Adverse Events (IMAE) and Cardiac events are considered AESIs in the 
context of this trial. 
Immune-Mediated Adverse Events of Special Interest 
Autoimmune diseases and immune-mediated clinical syndromes, emerging since the initiation of 
trial product, will be reported as potential IMAEs. 
So far, no signal has emerged from the diverse poxvirus constructs studied in the clinic, but the 
theoretical possibility exists that breaking the immune tolerance to self-antigens may induce 
autoimmune phenomena. This possibility deserves close vigilance.  

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The use of PD-1/L1 inhibitors in cancer treatment has expanded rapidly in the last few years.  It 
is imperative that clinicians are knowledgeable about the toxicities associated with these agents, 
their recommended management and how best to monitor for them.  In order to increase 
awareness, outline strategies and offer guidance on the recommended management of IMAEs in 
subjects treated with check-point inhibitors, ASCO in collaboration with the National 
Comprehensive Cancer Network (NCCN) developed clinical practice guidelines (Brahmer et al., 
2018) which should be referenced in addition to the mandatory atezolizumab United States 
Prescribing Information (USPI).  
Cardiac Adverse Events of Special Interest 
A Cardiac AESI is defined in this trial as: 
• 
Any cardiac sign or symptom (i.e., attributed by the investigator to be cardiac related), 
developed since the first vaccination 
• 
ECG abnormalities determined to be clinically significant, developed since the first 
vaccination 
AESIs should be reported to BN within 24 hours of the site’s awareness.  The collection period 
for AESIs begins once trial product is first initiated. An additional eCRF dedicated to potential 
IMAEs is linked to the (S)AE/AESI eCRF and must also be completed.   
8.1.4 Serious Adverse Events 
SAE is any untoward medical occurrence or reaction that at any dose: 
• 
Results in death 
• 
Is life-threatening 
The term "life-threatening" in the definition of "serious" refers to an event in which the 
subject 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. 
• 
Requires in-subject hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
*or is an otherwise an important medical event 
For purposes of this trial, an AE meeting the following criteria will also be considered Serious:  
• 
Suspicion of transmission of an infectious agent via trial product 
• 
Overdose of the trial product 
• 
**Potential drug-induced liver injury (DILI) 

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*Medical and scientific judgment should be exercised in deciding whether expedited 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 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually 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. 
**Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law and 
based on the following observations: 
• Treatment-emergent ALT or AST  3  baseline value in combination with total bilirubin 
 2  ULN (of which  35% is direct bilirubin) 
• Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice 
The following will NOT be considered SAEs: 
• 
Hospitalizations < 24 hours, or for planned surgeries or procedures. 
• 
Progression of underlying. 
• 
Death due to progression of underlying malignancy 
• 
A visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
• 
Elective surgery, planned prior to signing consent 
• 
Admissions as per protocol for a planned medical/surgical procedure 
• 
Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy). 
• 
Medical/surgical admission other than to remedy ill health and planned prior to entry 
into the trial. Appropriate documentation is required in these cases. 
• 
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g. lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 

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8.2 Assessment 
8.2.1 Relevant Medical History 
Relevant medical history, to include symptoms resulting from bladder cancer at the time of 
screening (not the bladder cancer diagnosis itself), will be collected and documented at the 
Screening Visit on the Medical History eCRF. 
Date and stage of the first diagnosis of bladder cancer must be recorded in the Cancer History 
eCRF ONLY.  Histology and supportive immunohistochemistry markers as well as relevant 
molecular markers, should be obtained when available and also documented on the Cancer 
History eCRF.   
Detailed description of all bladder cancer treatments (including drug and non-drug therapies, 
surgeries, radiation therapies) with their corresponding start and stop dates should be recorded on 
the applicable eCRF (either the Prior Cancer Medication eCRF or the Non-Drug therapies eCRF), 
with special attention to first-line treatment for locally advanced or metastatic UC. 
8.2.2 Prior and Concomitant Medication 
All medication for concomitant diseases, except homeopathic substances and dietary 
supplements, must be recorded in the Prior and Concomitant Medications eCRF and the subject’s 
medical record and should include information about the indication, dosage regimen, and onset 
and end of treatment.  
The following medication, taken within 90 days of the screening visit, will also be recorded in the 
Prior and Concomitant Medications eCRF and the subject’s medical record: vaccines, 
corticosteroids (via any route of administration), other immune-modulating drugs, 
immunoglobulin and/or any blood products, investigational drugs and depot preparations. 
8.2.2.1 Permitted Medications 
Any medications prescribed for concomitant disease or symptomatic relief of current disease are 
permitted with the exception of the ones listed in Section 8.2.2.2. 
For clarification purposes, the following medications and therapies are also allowed: 
Palliative radiotherapy for bone metastases or non-target soft tissue lesions completed > 7days 
prior to Screening imagining. 
Hormone-replacement therapy or oral contraceptives. 
Prophylactic antibiotics e.g., for prevention of urinary tract infection (UTI) or to prevent chronic 
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Influenza vaccination may be given during influenza season only (October – March) except live, 
attenuated vaccine (see Section 8.2.2.2) 
Prior non-experimental cancer vaccines and cellular immunotherapy indicated for superficial UC 
(for example Bacillus Calmette-Guérin [BCG]) or postsurgical adjuvant treatment of operable 
infiltrating UC. 
The use of inhaled, nasal, ophthalmic and topical corticosteroids, physiologic replacement doses 
of glucocorticoids (i.e., for adrenal insufficiency) and mineralocorticoids (e.g., fludrocortisone 
for adrenal insufficiency). 
The use of acute, low-dose, systemic corticosteroid medications (e.g., a one-time dose of 
dexamethasone for nausea or for prevention of hypersensitivity reactions to contrast agents). 
8.2.2.2 Prohibited Medications 
The following medications are prohibited during the trial, as well as prior to Day 1 based on the 
relative type of medication.  Additional medications may be deemed prohibited based on review 
during screening, if there is the risk to the subject or the ability to capture the trial outcome for 
the subject. 
• 
Any approved or experimental anti-cancer therapy including chemotherapy within 3 weeks 
prior to Day 1, and throughout the trial. 
• 
Treatment with any other investigational agent within 28 days prior to Day 1. 
• 
Therapeutic oral or IV antibiotics within 1 week prior to Day 1. 
• 
Live, attenuated vaccine including influenza vaccine (FluMist), within 4 weeks of Day 1 
and throughout the trial. 
• 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
anti-CTLA-4, anti-PD-1 and anti-PD-L1 therapeutic antibodies and throughout the trial. 
• 
Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, and anti-TNF agents) within 2 weeks prior to Day 1 and throughout the trial, 
or anticipated requirements for systemic immunosuppressive medications during the trial.  
8.2.3 Physical Examination 
Complete physical examination  
A complete physical examination will be performed at Screening. The examination includes a 
review of major organ systems as well as height and weight. The examination should be directed 
at finding evidence of any infections, tumors and lymphadenopathy. In addition, auscultation of 

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the heart and lungs to check specifically for signs of any heart condition will be performed. 
Complete physical exams may be performed at visits other than those indicated based on 
investigator’s discretion.  
Any clinically significant findings at the baseline physical examination will be recorded as 
medical history events, and any new or worsening clinically significant findings post-treatment 
will be captured as adverse events.  The only data captured in the eCRF for the physical 
examination itself will be the date it was performed. 
Targeted physical examination  
A targeted physical examination, guided by any signs or symptoms previously identified or any 
new symptoms that the subject has experienced since the last visit, is conducted at visits 
according to the Trial Procedure Schedule (Section 1.5) during the Treatment Phase.  Clinically 
significant findings from the treatment period physical examinations will be recorded as AE. 
8.2.4 Vital Signs 
Vital signs will be measured at visits according to the Trial Procedure Schedule (Section 1.5).  
Blood pressure and pulse rate should be obtained after the subject has been seated in an upright 
position for at least 5 minutes. Vital signs may be assessed at times other than those listed, based 
on investigator discretion. 
8.2.5 AEs 
AEs (e.g., feeling of ill-health, subjective symptoms and objective signs, intercurrent diseases, 
accidents, etc.) observed by the investigator and/or reported by the subject, regardless of 
relationship to trial product, must be assessed and recorded in the AE eCRF.  Only clinically 
significant findings from the treatment period physical examinations will be recorded as AE. 
AEs will be collected and documented at all visits of the active trial phase (including 
atezolizumab dosing visits) and if ongoing after the active trial phase followed until resolution or 
until the remote FU visit at the latest. 
SAEs and AESIs will be assessed and documented at all trial visits, including the remote FU 
Visit. Ongoing AESIs and SAEs will be followed up until resolution or achievement of stable 
clinical conditions. 
8.2.5.1 Progression of Underlying Malignancy 
For the purpose of this trial, progression of underlying malignancy is not considered an (S)AE. 
Hospitalization, prolonged hospitalization, or death due solely to the progression of underlying 
malignancy will be captured on the AE-section of the eCRF, but may NOT be reported as an 

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SAE. However, clinical symptoms of progression should be reported as (S)AEs if they cannot be 
determined to be exclusively due to the progression. 
Symptomatic deterioration may occur in the absence of radiographic evidence of tumor 
progression in some subjects. Alternatively, the disease progression may be so evident that the 
investigator may elect not to perform further assessments. In such cases, the determination of 
clinical progression is based on symptomatic deterioration. In these cases, efforts should be made 
to quantitatively document the progression of the underlying malignancy to the extent possible. 
8.2.6 Cardiac Assessment 
A standard 12-lead ECG will be performed at Screening. ECGs will be evaluated by the 
investigator for clinical significance. Troponin I will only be measured if clinically indicated. 
8.2.7 Safety Laboratory Measurements 
Safety laboratory (hematology and serum chemistry) is determined at the Screening Visit and at 
Visits 1-14 while urinalysis is determined at the Screening Visit and Visits 2, 4, 6-14 for all 
subjects. Thyroid function test (TSH, free T3 and free T4) will be performed at Screening and 
every 6 weeks through to Visit 14. If clinically indicated, Safety laboratory tests can be 
performed at any other visit(s). The safety laboratory measurements are performed at the site 
specific local laboratory. Laboratory normal ranges are provided by the local laboratory and filed 
in the Regulatory File. 
Safety laboratory parameters to be evaluated are in Table 4. 
Table 4: 
Protocol Required Safety Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Red blood cell (RBC) count 
Hemoglobin 
White blood cell (WBC) 
count; total and differential 
Platelet count 
Hematocrit 
Mean cell volume (MCV) 
Mean corpuscular 
hemoglobin (MCH) 
Red blood cell distribution 
width (RDW) 
Total protein 
Albumin 
Alkaline phosphatase 
Total bilirubin 
AST 
ALT 
Lactate dehydrogenase (LDH) 
Creatinine 
Blood urea nitrogen (BUN) 
Uric acid 
Glucose 
Phosphorous 
Bicarbonate 
Chloride 
Sodium 
Specific gravity 
Protein 
Glucose 
Blood 
Microscopic exam, if 
abnormal results are noted. 
 
 

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Hematology 
Biochemistry 
Urinalysis 
Potassium 
Calcium 
Amylase 
Lipase 
Thyroid Function Test Panel: 
• 
TSH 
• 
Free T3 
• 
Free T4 
The intensity of laboratory/systemic quantitatively measured toxicities will be graded according to 
the NCI-CTCAE version 5 toxicity scale in Appendix 2, Section 17.2. In case of other laboratory 
values not included in the NCI-CTCAE scale the general grading scale below will be used. 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
The following parameters will only be evaluated during the Screening Visit for assessment of 
inclusion/exclusion criteria: 
• 
INR 
• 
PT 
• 
aPTT 
• 
HIV 
• 
HBsAg 
• 
HCV 
8.2.8 Pregnancy 
Women of childbearing potential (WOCBP) and partners of participating males must be using 
acceptable method of contraceptive measures as outline in Appendix 1, Section 17.1 for 30 days 
prior to the first vaccination on Day 1, throughout the entire trial and for 5 months after the last 
dose of atezolizumab. WOCBP subjects will have a pregnancy test (serum or urine) at every visit 
including atezolizumab infusion only visits which occurs every 3 weeks. 
Any pregnancy (participating females and female partners of participating males) that occurs 
during trial participation must be reported using a clinical trial pregnancy form. To ensure subject 

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safety, each pregnancy must be reported to BN or designee within 24 hours of learning of its 
occurrence and should follow the procedures outlined in Section 8.3.3. 
8.3 Reporting 
8.3.1 Reporting of SAE 
All SAEs (initial and FU information) will be reported electronically through the Electronic Data 
Capture (EDC) platform within 24 hours of the discovery of the event. Manual SAE report forms 
are available in the Trial Reference Manual, however manual SAE report forms should be 
forwarded only in the event that electronic capturing is not functioning and must be entered on 
the AE eCRF when it again becomes available. BN or designee may request FU and other 
additional information from the Investigator (e.g., hospital admission/discharge notes, laboratory 
results, etc.). 
The investigator should not delay reporting because of missing information. Nonetheless, the 
report should be as complete as possible. This initial notification should include, at a minimum, 
sufficient information to permit identification of the following:  
• 
The reporter (investigator’s name and contact information) 
• 
The subject 
• 
Involved trial product 
• 
AE(s) 
• 
Seriousness criterion and/or criterion for AESI 
• 
Date of onset 
• 
Investigator assessment of causality 
The collection of SAE/AESI begins at the time the subject signs informed consent and continues 
for 30 days following administration of the last dose of trial product for unrelated SAEs/AESIs, 
and 100 days for related SAEs/AESIs after the last dose of trial product, due to the possibility of 
a delayed immune effect of anti-PD-1/L1 agent (atezolizumab). 
All SAEs, irrespective of the treatment received by the subject, must be reported to BN’s PV 
department within 24 hours of the investigator learning of the event.  
All deaths should be reported with the primary cause of death as the SAE term, as death is 
typically the outcome of the event, not the event itself. The primary cause of death on the autopsy 
report should be the term reported. Autopsy and postmortem reports must be forwarded to BN’s 
PV department as outlined above. 
If trial product is discontinued because of an SAE, this information must be included in the SAE 
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Investigators must report SAEs to their governing IRBs in writing as soon as possible and in 
accordance with national and local laws and regulations. 
8.3.2 Reporting of AESIs 
As noted in Section 8.1.3, IMAEs and cardiac events are considered AESIs as well as the AESI 
requirements from the manufacturer of Tecentriq®.  AESIs occurring throughout the reporting 
period are to be recorded on the AE eCRF by marking the appropriate tick box as well as the 
(S)AE/AESI eCRF, regardless of seriousness or attribution. AESIs have to be reported 
immediately after detection. An automatic email notification will be sent to the relevant project 
members as soon as an AESI has been reported in the EDC. In addition to the above mentioned 
eCRFs, an IMAE eCRF is also linked to the (S)AE / AESI eCRF in the EDC and must be 
completed by the investigator when reporting an IMAE AESI. 
Appendix , Section 17.3 outlines the reporting process and timelines for AESIs. 
8.3.3 Reporting of Pregnancies 
Trial product exposed pregnancies cannot be excluded with certainty. Subjects who are 
discovered to be pregnant prior to the first vaccination will be excluded from the trial and 
regarded as screen failures. Subjects who are discovered to be pregnant during the active trial 
period must not receive additional doses of CV301 or atezolizumab, but may continue other trial 
procedures at the discretion of the investigator. All reports where the embryo or fetus may have 
been exposed to the trial product (either through maternal exposure or transmission of trial 
product via semen following paternal exposure) should be followed-up until delivery in order to 
collect information on the outcome of the pregnancy. 
Subjects should be instructed to notify the investigator if it is determined – also after completion 
of the trial – that they became pregnant either during the trial or within 30 days after receiving the 
last dose of CV301 dose or 5 months after the last dose of atezolizumab. 
If a subject becomes pregnant during the active trial period this must be reported to BN on a 
manual Pregnancy Notification Report Form (available in the Site Reference Manual) within 24 
hours of the investigator’s becoming aware of the event.  
Female subjects or female partners of male subjects will be counseled as to any possible known 
risks to either the partner or the child. At the current time, no pregnancies have been reported for 
subjects treated with CV301 and therefore no data exist that would identify risks to partner or 
child.  It is the responsibility of the investigator to counsel the subject on the identified risks of 
atezolizumab according to the USPI as well as disclose any known risks prior to the subject 
consenting to receive treatment with atezolizumab. 
A pregnancy should be followed till outcome, and the health status of the mother and child 
including date of delivery and the child’s gender and weight should be reported to BN as soon as 

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possible after delivery on a Pregnancy Outcome Report Form (available in the Site Reference 
Manual). The female partner should sign the Pregnant Partner Informed Consent Form for follow 
up.  
Any event during pregnancy fulfilling the criteria for an SAE will be reported as SAE to BN PV 
department. However, hospitalization for delivery is a prospectively planned hospitalization and 
is not considered a SAE per se. Pregnancies resulting in an abnormal outcome (i.e., congenital 
abnormality, birth defect, or infant death) should be reported as SAEs within 24 hours of the 
investigator becoming aware of the event. 
9 Statistical Considerations 
This is a single-arm, multi-center, two-cohort Phase 2 clinical trial to assess the safety and 
preliminary efficacy of CV301 in combination with PD-1/L1 blockade in subjects with locally 
advanced or metastatic urothelial cancer including the bladder, ureter, or renal pelvis.  The trial 
will be performed as a two-stage design (Simon, 1989) within the following two cohorts: 
Cohort 1: Ineligible for cisplatin-containing chemotherapy  
Cohort 2: Previously treated with standard first-line cisplatin-based chemotherapy, PD-1/L1 
naïve 
The goal is to demonstrate that CV301 plus atezolizumab can induce objective responses in 
subjects with locally advanced or metastatic urothelial cancer in at least one of the two cohorts. 
Presentation of results will occur by cohort for efficacy and exploratory endpoints, and by cohort 
and overall for safety, disposition, demographic, and baseline characteristic endpoints.  In 
general, continuous endpoints will be analyzed using mean, standard deviation, median, 
minimum, and maximums.  Categorical endpoints will be analyzed using frequencies and 
percentages.   
9.1 Endpoints 
See Protocol Synopsis (Section 1.4). 
9.2 Sample Size Calculation 
Refer to Protocol Synopsis (Section 1.4). 
9.3 Analysis Populations 
For the purpose of statistical analysis, there will be 2 analysis populations: Full Analysis Set 
(FAS) and the Efficacy Evaluable Set (EE). 

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The FAS consists of all subjects taking any amount of trial vaccine, whether MVA-BN-CV301 or 
FPV-CV301. The FAS will be the primary population for all analyses.  
The EE Set consists of all subjects from the FAS who received 2 prime doses of  
MVA-BN-CV301 (Weeks 1 and 4).  
The EE population will be used in sensitivity analyses for efficacy.   
Subjects who failed to meet the EE Set criteria will be replaced unless 4 or more responses in 
Cohort 1 (or 3 or more responses in Cohort 2) have been observed for the FAS population, or the 
number of responders will still be less than 4 in Cohort 1 (or 3 in Cohort 2) even if all 
replacement subjects would be responders. If there are more than 14 evaluable subjects in 
Cohort 1 (or 13 in Cohort 2) at the end of Stage 1 analysis, or more than 33 in Cohort 1 (or 35 in 
Cohort 2) evaluable subjects at the end of Stage 2 analysis, primary evaluation will be based on 
the first 14 (or 13) accrued or first 33 (or 35) accrued FAS subjects.    
9.4 Subject Disposition 
The number and percent of subjects who meet all protocol inclusion and exclusion eligibility 
criteria, who discontinue trial product, and reason for trial product discontinuation will be 
presented using the FAS. Subject participation by site will also be presented.   
9.5 Subject Characteristics 
Subject characteristics including demographics, disease characteristics, prior cancer therapies, 
and relevant medical history will be summarized for the purpose of describing the subject 
population using the FAS. 
9.6 Prior/Concomitant Medications 
All concomitant medications (including Long Term FU anti-cancer treatments) and prior 
medications will be coded to Anatomic-Therapeutic-Chemical (ATC) drug classes and preferred 
drug names using the WHO Drug Dictionary. The incidence of prior and concomitant medication 
usage will be summarized by ATC class and preferred drug names for the FAS. 
9.7 Efficacy Analysis 
9.7.1 Primary Efficacy Analysis 
The ORR is defined as the proportion of subjects with an objective tumor response (CR or PR) 
based on RECIST 1.1 evaluations as performed by the investigator.  Based on prior published 
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Cohort 1: In the first stage, 14 subjects will be accrued. If there are 3 or fewer responses in these 
14 subjects, the cohort will be stopped. Otherwise, 19 additional subjects will be accrued for a 
total of 33. The null hypothesis will be rejected if 13 or more responses are observed in 33 
subjects. This design yields an actual type I error rate of 0.0244 and power of 0.7027 when the 
true ORR is 0.43 for the combination. 
 
Cohort 2: In the first stage, 13 subjects will be accrued. If there are 2 or fewer responses in these 
13 subjects, the cohort will be stopped. Otherwise, 22 additional subjects will be accrued for a 
total of 35. The null hypothesis will be rejected if 10 or more responses are observed in 35 
subjects. This design yields an actual type I error rate of 0.0249 and power of 0.7092 when the 
true ORR is 0.33 for the combination. 
 
In the case that the number of responses required to move to Stage 2, individually per cohort, is 
met in the FAS population, the study will move to Stage 2 without enrolling the full EE Set.  If 
Stage 1 results are not clear after enrolling the prescribed number of Stage 1 subjects in the FAS, 
enrollment will continue until the EE Set meets the prescribed number of Stage 1 subjects for the 
interim futility analysis.  In the event continuing enrollment of the EE Set would still not produce 
a positive outcome for Stage 1, the cohort will be discontinued without meeting the full Stage 1 
sample size for the EE set. 
For the final primary efficacy analysis, the number and percent of subjects with OR, and in each 
category of objective tumor response, will be summarized based on the FAS. The two-sided 90% 
exact binomial confidence interval for the ORR will be calculated using the Clopper-Pearson 
method. 
Sensitivity analyses will be performed based on a repeated analysis using the EE Set, as well as 
any potential immune-related responses observed. In case these immune-related responses are 
observed, ORR analyses using iRECIST criteria will also be provided. For iRECIST, complete or 
partial responses are still able to be achieved after an initial unconfirmed progression, whereas 
with RECIST 1.1 once any evidence of progression is recorded, no further responses are able to 
be evaluated.  For subjects who are not evaluated by iRECIST criteria, their tumor response 
based on RECIST 1.1 response guidelines will be used. 
9.7.2 Secondary Efficacy Analyses 
9.7.2.1 Progression-Free Survival 
PFS is defined as the time interval from first treatment to objective tumor progression or death. 
Accordingly, the precise definition of progression and the timing of CT scans to document 
progression are very important. Every effort must be made to assure that timeframes for FU CT 
scans are achieved. Assessments must be adequate to evaluate target lesions, non-target lesions, 
and to search for new lesions.  

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The secondary endpoint of PFS will be based on the investigator’s assessment using 
RECIST 1.1 response guidelines. PFS will be defined as the time from the day of first treatment 
with trial product to the start of disease progression or death (any cause), whichever occurs first. 
Subjects who do not have disease progression or have not died will be censored at the date when 
the last tumor assessment determines a lack of progression. If a subject begins a new anti-cancer 
therapy or has radiotherapy or surgery at a lesion site prior to documented progression (or death), 
the subject will be censored at the last assessment where the subject was documented as 
progression free prior to the intervention.  
The Kaplan-Meier curve for PFS and the median PFS will be presented for the FAS Set.  
Additionally, an investigator assessed PFS analysis that includes both investigator-judged PD 
according to RECIST 1.1 and symptomatic deterioration will be provided. 
A binary endpoint for PFS will also be analyzed at milestone time points. The number and 
percentage of subjects who are progression free based on the above definition at 6, 9, 12, 18, and 
24 months will be summarized within the FAS. The two-sided 90% exact binomial confidence 
interval for the PFS at each time point will be calculated using the Clopper-Pearson method.  
A recently published meta-analysis concluded that in checkpoint inhibitor trials 6-month PFS rate 
is recommended as an endpoint because it is the best predictor of 12-month OS rate (Ritchie et 
al., 2018). In the absence of prospective validation, the decision adopted is to retain 6-month PFS 
rate as a secondary endpoint with the aim of complement the primary endpoint ORR in the 
interpretation of trial results as a whole. 
In case some additional immune-related responders are observed, PFS analysis using iRECIST 
criteria will be performed. The iRECIST modification requires a confirmation of PD at least 
4 weeks later with imaging; once confirmed, the date of progression is defined as the first date 
that the total tumor burden was shown to have increased by at least 20% compared with the nadir. 
For subjects who are not evaluated by iRECIST criteria, their disease progression based on 
RECIST 1.1 response guidelines will be used.    
9.7.2.2 Overall Survival 
OS is defined as the time interval from first treatment to death of any cause. Subjects who are 
alive will be censored at the last known date subject is alive. The 12-month OS rate and the 
product-limit estimate of median survival, as well as their 90% confidence intervals will be 
summarized.  A Kaplan-Meier curve will summarize OS graphically. The 18-month and  
24-month survival rates will also be provided along with their 90% CIs. 
9.7.2.3 Duration of Response 
Duration of response is defined as the time from response (CR or PR, whichever occurs first) to 
investigator assessed progression using RECIST 1.1 or death, and will be summarized based on 

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the number of subjects with response in the FAS. Subjects who do not have disease progression 
or have not died will be censored at the date when the last radiographic tumor assessment 
determines a lack of progression. 
Duration of response will be summarized using the product-limit estimate of median survival 
along with its 90% confidence interval.  The Kaplan-Meier curve will summarize duration of 
response graphically. 
In case some additional immune-related responders are observed, duration of response analyses 
using iRECIST criteria will be provided. For subjects who are not evaluated by iRECIST criteria, 
their tumor response based on RECIST 1.1 response guidelines will be used. 
9.7.3 Subgroup Analyses 
Each cohort will be analyzed individually for the efficacy endpoints as the background response 
rates are known to be different in each group. In addition, small sample size prevents further 
subgroup analyses from being possible.     
9.8 Exploratory Analyses 
Analyses of exploratory endpoints will be based on the FAS, where both baseline and at least one 
post-baseline assessment are available.  Missing data will not be imputed.  Analyses will focus on 
comparing the post-baseline values with the baseline values.  Correlation between tumor response 
and immune responses will be explored. 
Continuous data will be summarized via mean (and 95% CI), standard deviation, median, 
minimum, and maximum by visit where samples are collected per trial schedule.  In case of log-
normal data, log transformations may be performed and summarized with the geometric means in 
place of the arithmetic means and 95% CIs. 
9.9 Safety Analysis 
Safety will be monitored by performing physical examinations including vital signs, routine 
laboratory measurements, as well as by evaluating AEs. AEs will be followed as described in 
Section 8 of this protocol.   
Safety will be evaluated by the incidence of Treatment-Emergent Adverse Events (TEAEs) and 
SAEs, physical examination, laboratory abnormalities and percentage of subjects experiencing 
dose modifications, interruptions, and/or discontinuation, based on the FAS. 
9.9.1 Adverse Events 
Adverse events will be recorded on the case report forms by the Investigator using verbatim terms 
that best describe the event. A TEAE is an adverse event with an onset on or after initiation of 

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trial product, or an adverse event present at initiation of trial product that worsens (i.e., increase 
in severity: On-Study Grade > Baseline Grade; or relationship to trial product is reported as a 
possible, probable, or definite). Verbatim descriptions of TEAEs will be mapped to Medical 
Dictionary for Regulatory Affairs (MedDRA) Version 20 or newer and graded according to NCI-
CTCAE, Version 5. All TEAEs (to include SAEs and AESIs) occurring from the first dose 
through 30 days of last dose of trial product, if unrelated to trial product or non-serious, and all 
trial product related SAEs and AESIs through 100 days of last dose of trial product, will be 
summarized by system organ class, and preferred term and further by NCI-CTCAE grade. On 
subject-based AE tables, for each specific TEAE, a subject will be counted only once under the 
maximum severity experienced. Similar summaries will be provided for all Grade 3 or higher 
TEAEs, SAEs, and AEs that lead to discontinuation of trial product. All AEs will be included in 
the subject listings. Separate listings of subjects that discontinue trial product due to an AE, and 
listings of subjects with SAEs and deaths will also be presented. 
9.9.2 Laboratory Data 
Laboratory toxicities will be defined based on universal normal ranges and NCI-CTCAE, 
Version 5.0. The number and percentage of subjects will be summarized by grade using the most 
severe grade by cycle. Clinically significant changes in laboratory values will be summarized. 
Laboratory values will be listed, with Grade 3 or 4 values flagged.  
9.9.3 Treatment Exposure 
Treatment exposure to CV301 in combination with atezolizumab will be provided. Number of 
CV301 injections and atezolizumab infusions administered, duration of exposure, and number of 
subjects with dose interruptions will be summarized based on the FAS. 
Missing Data 
For duration of OS, PFS, or duration of response, subjects who are lost to FU will be analyzed as 
censored observations on the date of last known alive for OS, or last radiographic assessment for 
PFS and duration of response.  Missing or partial dates will be imputed for prior/concomitant 
medications, adverse events, and cancer history.  Details will be provided in the statistical 
analysis plan. 
9.10 Multiplicity 
Due to the two-cohort, two-stage design of this Phase 2 trial, the primary endpoint of objective 
response rate will be tested multiple times.  To account for this, the sample size for each cohort 
was based on a one-sided nominal alpha of 0.025 and 70% power.  As each cohort represents an 
independent test, the overall trial-wide type I error rate would remain at or below 0.05 (one-
sided).  Based on simulations with the two-stage, two-cohort design, the overall type-1 error rate 
will be approximately 4.7%, and the power for the trial indicating at least one of the two cohorts 
will be positive given the alternative hypotheses are true, is approximately 91%. 

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9.11  Interim Analysis 
Due to the two-stage design, an interim analysis with pre-specified stopping rules will be 
performed within each cohort.  The ORR will be calculated after the first stage subject accrual is 
complete, separately for each cohort.  Although the primary efficacy analysis will be performed 
on the FAS, if it is unclear within the first 14 FAS subjects in Cohort 1 (or 13 in Cohort 2) that 
the criteria are met for futility for Stage 1, enrollment will continue in the cohort until the full 
Stage 1 sample size is reached for the EE Set.  If, even with enrolling additional subjects for the 
EE Set and those subjects all being responders, the cohort would not be able to reach the required 
number of responders to move to Stage 2, the cohort will be discontinued without reaching the 
full size of the EE Set. 
The decision rules are as follows: 
Figure 1: 
Interim Analysis Decision Tree 
 
The decision to stop an individual cohort will be independent for each cohort.   
Enroll required Stage 1 # of  FAS 
subjects
(14 for Cohort 1, 13 for Cohort 2)
# of FAS responders + # EE 
subjects remaining to be enrolled 
< required # of responders
Discontinue Cohort
# of FAS responders + # 
EE subjects remaining to be 
enrolled ≥ required # of 
responders
Continue to enroll 
subjects to meet full 
Stage 1 sample size 
for EE Set
≥4 responses in EE 
Set for Cohort 1
(or ≥3 for Cohort 2)
Move to Stage 2 to 
reach full sample size 
for EE Set
<4 responses in EE 
Set for Cohort 1 
(or <3 for Cohort 2)
Discontinue Cohort
≥4 responses in FAS 
for Cohort 1
(or ≥3 for Cohort 2)
Move to Stage 2 to 
reach full sample size 
for FAS

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9.12 Timing of Analyses 
The first post-treatment objective radiographic response assessment by the investigator will occur 
approximately 10 weeks after first treatment, with the second occurring 12 weeks later at the 
Week 22 visit.  For subjects who have completed multiple scans, the best objective response will 
be used.   
If at least 4 objective responses in Cohort 1 (or 3 objective responses in Cohort 2) are observed in 
the FAS prior to the end of Stage 1, enrollment of Stage 2 subjects will continue regardless of the 
full enrollment of the EE Set.  If the results of Stage 1 are unclear based on full enrollment of 
Stage 1 in the FAS, enrollment will continue until the full Stage 1 sample size is reached for the 
EE Set.  If success is not possible in Stage 1, even with continuing enrollment until the full EE set 
was reached and all additional subjects were responders, the cohort will be discontinued without 
meeting full enrollment of the EE Set.  In addition, the timing of the initiation of Stage 2 in a 
cohort need not depend on the completion of Stage 1 in the opposite cohort. 
The end of Stage 2 analyses will again be based on best objective response outcomes.  If the 
required number of responses are observed for a positive outcome in Stage 2 for the FAS, 
enrollment will be stopped and the trial will be declared a success.  If it is unclear if the study is 
successful based on the FAS subjects, additional subjects will be enrolled until the full sample 
size for Stage 2 is reached in the EE Set.  Because objective radiographic response rates may 
increase with further follow up, the data may be analyzed with updates if subsequent follow up 
demonstrates additional objective responses.  
Final analyses will occur when all subjects have either completed the 2-year treatment period, or 
have progressed. 
9.13 Changes in Statistical Methods 
All changes in statistical methods from that described in the Statistical Analysis Plan will be 
documented in the Clinical Study Report. 
10 Ethical Aspects 
10.1 Ethical and Legal Regulations 
This trial will be conducted in a manner consistent with the principles that have their origin in the 
Declaration of Helsinki and in accordance with FDA regulations (21 CFR § 11, 50, 54, 56, and 
312), with the ICH GCP guidelines (ICH E6), as well as with any and all applicable federal, state 
and/or local laws and regulations. 

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10.2 Approved by IRB 
Before enrollment of subjects into the clinical trial, as required by federal regulations 
(21 CFR § 56), ICH GCP and local regulations, the current protocol and ICF will be reviewed 
and approved by an appropriate IRB. A letter documenting the IRB or IEC approval must be 
received by the sponsor before the initiation of the trial at a clinical site. Amendments to the 
protocol will be subject to the same requirements as the original protocol. 
The Investigator will submit a progress report at least once yearly to the IRB. However, the 
frequency of these reports will depend on IRB requirements. As soon as possible after completion 
or termination of the trial, the Investigator will submit a final report to the IRB per the IRB 
requirements, and in compliance with FDA regulations and ICH GCPs.  
The Investigator, the sponsor, or designee shall promptly notify the IRB or IEC of any SAEs, or 
any other information that may affect the safe use of the trial drug during the course of the trial, 
per the IRB local requirements, and in compliance with FDA regulations and ICH GCPs. 
Copies of all correspondence between the investigator and the IRB must be forwarded 
immediately to the Sponsor or designee. In case of withdrawal of IRB approval of the trial, the 
Sponsor or designee has to be contacted immediately by facsimile, e-mail or telephone. 
10.3 Confidentiality and Data Protection 
Information on maintaining subject confidentiality in accordance with individual local and 
national subject privacy regulations must be provided to each subject as part of the informed 
consent process either as part of the ICF or as a separate signed document (for example, in the 
US, a site-specific Health Insurance Portability and Accountability Act [HIPAA] consent may be 
used). 
The Investigator or designee must explain to each subject that for the evaluation of trial results, 
the subject’s protected health information (PHI) obtained during the trial may be shared with BN 
and its designees, regulatory agencies, and IRBs. As the trial Sponsor, BN will not use the 
subject’s PHI or disclose it to a third party without applicable subject authorization. It is the 
Investigator’s or designee’s responsibility to obtain written permission to use PHI from each 
subject. If a subject withdraws permission to use PHI, it is the Investigator’s responsibility to 
obtain the withdrawal request in writing from the subject and to ensure that no further data will 
be collected from the subject. Any data collected on the subject before withdrawal will be used in 
the analysis of trial results. 
During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations. 

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11 Informed Consent 
The investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the trial, including answering any questions the subject may have 
throughout the trial and sharing in a timely manner any new information that may be relevant to 
the subject’s willingness to continue his or her participation in the trial. 
No subject can participate in the trial without first having given informed consent in writing. The 
investigator or his delegate will inform the subject clearly and completely, verbally and in 
writing, about the purpose, procedures and the potential benefits and risks of participation in the 
trial prior to the initiation of any trial specific procedure. The subject will also be informed of the 
potential future use of biological samples collected during the trial.  
The ICF will be used to explain to the subject in simple terms the potential risks and benefits of 
trial participation and to document that the subject is satisfied with his or her understanding of the 
risks and benefits of participating in the trial. 
The investigator is responsible for ensuring that informed consent to participate in the trial is 
given by each subject (or their legal representative). This includes obtaining the appropriate 
signatures and dates on the ICF prior to the performance of any protocol procedures and prior to 
the administration of trial drug. 
One signed copy of the ICF (including HIPAA) must be given to each subject and one signed 
copy must remain in the Investigator Site File and be available for verification by the monitor, 
Sponsor/CRO auditor or competent regulatory authorities at any time. 
Subjects must be informed unequivocally that they may refuse participation in the trial and that 
they may withdraw from the trial at any time and for whatever reason and that withdrawal of 
consent will not affect their subsequent medical treatment or relationship with the treating 
physician. 
Subjects also consent to authorize the monitor, quality assurance personnel and regulatory 
authorities to inspect source documents for data verification and quality assurance purposes. Such 
verifications will always be conducted at the clinical trial site and under the ethical supervision of 
the investigator. To the degree possible, confidentiality of the subject’s PHI will be maintained. 
The Informed Consent will be prepared in accordance with ICH GCP guidelines and must be 
approved by the appropriate IRB. 

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12 eCRF and Retention of Records 
12.1 eCRF 
eCRFs will be used to collect the clinical trial data and must be completed for each screened 
subject. All data must be accurately recorded such that the information matches the data 
contained in subject’s medical records (e.g., physicians’ notes, nurses’ notes, clinic charts, and 
other trial-specific source documents). Authorized trial site personnel (i.e., listed on the 
Delegation of Authority form) will complete training based on the electronic data capture (EDC) 
system for the trial, as well as complete the trial-specific eCRFs according to the eCRF 
Completion Guidelines (provided as a separate document). The Investigator will ensure that the 
eCRFs are accurate and completed within 5 days of each subject’s visit. At all times, the 
Investigator has final responsibility for the accuracy and authenticity of all clinical data. 
The eCRFs exists within an EDC system with controlled access managed by BN or its authorized 
representative for this trial. Trial staff will be appropriately trained in the use of trial-specific 
eCRFs and application of electronic signatures before the start of the trial, and before being given 
access to the EDC system. Original data and any changes of data will be recorded using the EDC 
system, with all changes tracked by the system and recorded in an electronic audit trial per CRF.  
Note, only changes entered into the eCRF fields, themselves, can be used for reporting of trial 
results.  Information entered into the change logs (for example, query responses) will be for 
documenting reasons for changes only.  
The Investigator attests that the information contained in the eCRFs is true by providing 
electronic signature within the EDC system. After database lock, the Investigator will receive a 
copy of the subject data (e.g., paper, CD-ROM or other appropriate media) for archiving at the 
clinical trial site. 
12.2 Retention of Records 
The Investigator/trial staff must maintain adequate and accurate records to enable the conduct of 
the trial to be fully documented and the trial data to be subsequently verified. All essential 
documents, as listed in ICH GCP guidelines, will be retained by the Investigator for at least 
2 years after the date the last marketing application is approved for the drug in the indication 
being investigated and until there are no pending or contemplated marketing applications; or, if 
no application is to be filed or if the application is not approved for such indication, until 2 years 
after formal discontinuation of clinical development of the drug.  
The Investigator must notify and obtain written approval from BN before destroying any clinical 
trial documents or images (e.g., scan, radiograph, ECG tracing) at any time. The Sponsor will 
inform the Investigator of the date that the trial records may be destroyed or returned to BN.  

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Should an Investigator wish to assign trial records to another party, advance written notice will be 
given to the Sponsor. BN must also be notified in advance and provide express written approval 
of any change in the maintenance of clinical trial documents, should the Investigator choose to 
move trial records to another location.   
If the Investigator cannot guarantee the aforementioned archiving requirements at the clinical 
trial site for all such documents, special arrangements must be made between the Investigator and 
BN to store these documents in secure sealed containers away from the clinical trial site. These 
documents must be able to be returned in their secure sealed containers to the clinical trial site for 
auditing purposes. 
13 Monitoring of the Trial 
Representatives of BN or its designee (e.g., CRO) will monitor this trial until completion. 
Monitoring will be conducted according to the monitoring plan which must be approved by BN. 
The monitoring plan will specify in detail the items for source data verification and other tasks, to 
be performed by the CRA during the clinical trial site visit. 
Monitoring will be conducted through personal visits with the Investigator and site staff, remote 
monitoring, as well as any appropriate communications by mail, fax, email, or telephone. The 
purpose of monitoring is to ensure that the trial is conducted in compliance with the protocol, 
SOPs, and other written instructions and regulatory guidelines, and to ensure the quality and 
integrity of the data. This trial is also subject to reviews or audits. 
To assure the accuracy of data collected in the eCRFs, it is mandatory that the monitor have 
access to all original source documents, including all electronic medical records (EMR) at 
reasonable times and upon reasonable notice. During the review of source documents, every 
effort will be made to maintain the anonymity and confidentiality of all subjects during this 
clinical trial.  
14 Audits and Inspections 
Site audits may be carried out at any time during or after completion of this trial by the Quality 
Assurance Department at Bavarian Nordic or designee. All trial-related documentation must be 
made available to the designated auditor. The Investigator agrees to allow the IRB, 
representatives of BN, its designated agents and authorized employees from local, state, or 
Regulatory Authority (e.g., FDA) to inspect the facilities used in this clinical trial at any time 
before, during, or after completion of the clinical trial and, for purposes of verification, allow 
direct access to the hospital or clinic records of all enrolled subjects. A statement to this effect 
will be included in the informed consent and permission form authorizing the use of protected 
health information. In the event of such an inspection, BN will be available to assist in the 
preparation. All pertinent trial data should be made available as requested for verification, audit, 
or inspection purposes. 

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15 Responsibility of the Investigators 
The Principal Investigator (PI) agrees to carry out the trial in accordance with the guidelines and 
procedures outlined in this clinical trial protocol. The PI especially consents to strictly adhere to 
the ethical principles mentioned in Section 10.1 of this protocol. 
Changes to the protocol require a written Protocol Amendment to be submitted and approved by 
the local IRB, the Coordinating Investigator and the PI of the respective clinical trial site.  
Changes are allowed only if the trial value is not reduced and if they are ethically justifiable. The 
amendment must be passed on to all participating investigators with the obligation to adhere to its 
provisions. If warranted, the subject information has to be changed accordingly.  
It is within the responsibility of the investigator that the CRF has to be completed in a timely 
manner after each subject visit and signed after the subject has finished the trial for each subject 
participating in the trial. 
At the conclusion of the trial, the investigator will return all partly used, unused and empty 
vaccine containers to the Sponsor or the vaccine containers will be destroyed at the clinical trial 
site according to local legal requirements.  
The investigator may ask to terminate the trial due to administrative or other reasons. If this 
should be the case, appropriate measures which safeguard the interests of the participating 
subjects must be taken after verification and consultation with the PI. 
Each investigator will maintain appropriate medical and research records for this trial, in 
compliance with ICH GCP (E6), Section 4.9, and regulatory and institutional requirements for 
the protection of confidentiality of subjects. He/she will permit authorized representatives of the 
Sponsor and regulatory agencies to review (and, when required by applicable law, to copy) 
clinical records for the purposes of quality assurance reviews, audits, and evaluation of the trial 
safety and progress. 
The PI agrees to follow the detailed publication policy included in the clinical trial agreement. 
By signing this protocol, the PI confirms that he/she has read the entire clinical trial protocol, 
agrees to its procedures, and will comply strictly with the formulated guidelines. 

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16 References 
CV301 (MVA-BN-CV301 and FPV-CV301) Investigator Brochure. 
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NECCHI, A., GERRITSEN, W., GURNEY, H., QUINN, D. I., CULINE, S., 
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INVESTIGATORS, K.-. 2017. Pembrolizumab as Second-Line Therapy for Advanced 
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plus best supportive care compared with best supportive care alone after a platinum-
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BEUKEMA, E. L., BROWN, M. P. & HAYBALL, J. D. 2006. The potential role of fowlpox 
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17 Appendices 
17.1 Appendix 1: Contraception Eligibility Criteria for Female and Male 
Subjects 
A woman is considered of childbearing potential unless post-menopausal (defined as ≥12 months 
without a menstrual period) or surgically sterilized.  A female subject is eligible to participate if 
she is not pregnant (as confirmed by a negative βhCG test), not lactating, and at least one of the 
following conditions applies: 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, 
injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP subject or 
male subject’s WOCBP partner. Female partners of male subjects participating in this trial may 
use hormone based contraceptives as one of the acceptable methods of contraception since they 
will not be receiving study drug 
Nonhormonal IUDs, such as ParaGard 
Tubal ligation  
Vasectomy 
Complete Abstinence* 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence 
are not required to use a second method of contraception, but female subjects must continue to 
have pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence. 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
Diaphragm with spermicide 
Cervical cap with spermicide 
Vaginal sponge 
Male condoms with spermicide 
Male Condom without spermicide  
Progestin only pills by WOCBP subject or male subject’s WOCBP partner  
Female Condom** 
** A male and female condom must not be used together

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17.2 Appendix 2: NCI Common Terminology Criteria For Adverse Events (NCI 
CTCAE version 5). 
A copy of the CTCAE version 5 can be downloaded from the NCI website at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf 
Should a subject experience any AE not listed in the CTCAE version 5, the following grading 
system should be used to assess severity:  
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
 

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17.3 Appendix 3: Algorithm for Reporting of AESIs 
 
 
AE 
AE serious? 
Report Event in the AE Section of 
the eCRF. 
Refer to Section 8.1.3 for Reporting 
SAEs. 
Investigator reports AESI to BN PV 
within 24 hours. 
Is the AE an AESI 
according to definition 
in Section 8.1.3 
Complete AE reporting. 
Yes 
Yes 
No 
Is the AESI related 
to IMP? 
Complete AESI reporting 
No 
Database/file AESI 
No 
Yes 

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17.4 Appendix 4: RECIST 1.1 Criteria 
The best overall response is the best response recorded from the start of treatment until 
disease progression/recurrence, taking as reference for progressive disease the smallest 
measurements recorded since treatment started.  The patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
Target Lesions 
Non-target 
Lesions 
New Lesions* 
Overall 
Response 
Best Overall 
Response when 
confirmation is 
required 
CR 
CR 
No 
CR 
> 4 week 
confirmation** 
CR 
Non-CR/non-PD 
No 
PR 
> 4 week 
confirmation** 
CR 
Not evaluated 
No 
PR 
> 4 week 
confirmation** 
PR 
Non-CR/non-
PD/not evaluated 
No 
PR 
> 4 week 
confirmation** 
SD 
Non-CR/non-
PD/not evaluated 
No 
SD 
Documented at 
least once 4 
weeks from 
baseline** 
PD 
Any 
Yes or no 
PD 
No prior SD, PR, 
or CR 
Any 
PD*** 
Yes or no 
PD 
No prior SD, PR, 
or CR 
Any 
Any 
Yes 
PD 
No prior SD, PR, 
or CR 
*See RECIST 1.1 Manuscript for further details on what is evidence of new lesions. 
**Only for non-randomized trials with response as primary endpoint 
***In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Confirmation: To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed at least 4 weeks after the criteria 
for response are first met. 

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17.5 Appendix 5: Protocol Changes 
Protocol Edition 2 
Minor administrative and grammatical updates. 
Throughout the protocol, changed IMP and trial treatment to trial product. 
List of abbreviations was updated 
 
Section 1.4, Synopsis, Number of Sites 
Updated to 12 
Rationale 
Increased for enrollment purposes. 
Section 1.4, Synopsis, Exploratory Objectives, bullet #5 
Added Analysis of tumor DNA for Tumor mutational burden; DNA damage response gene 
mutations, MSI status, MMR deficiency status; deleted ctDNA 
Rationale 
Corrected to what may be analyzed. 
Section 1.4, Synopsis, Secondary endpoints, Safety 
Added description of safety measurements.  
Rationale 
To show what safety measurements will be evaluated. 
Section 1.4, Synopsis, Inclusion for All Subjects, #1 
Added: The ICF must be signed prior to any protocol specific assessments. 
Rationale 
Added for further clarification. 
Section 1.4, Synopsis, Inclusion for All Subjects, #3 
Added: Histologically or cytologically documented locally advanced (T4b, any N M0; or any 
T, N 1−3 M0) or metastatic (M1, Stage IV; or metastatic recurrence after locoregional 
treatment) UC (including renal pelvis, ureters, urinary bladder, urethra). 

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Note about the change in the definition of Locally Advanced from TNM v7 to the 
current v8, while all those cases were Stage IV in v7, with TNM v8 they are 
reclassified as Stage IIIA (T1-4a N1 M0) and Stage IIIB (T1-4a N2-3 M0). 
Rationale 
Added for further clarification. 
Section 1.4, Synopsis, Inclusion for All Subjects, #7 
Added: Must be on acceptable method for at least 30 days prior to 1st dose of trial 
product and to continue its use for 5 months after the last dose of atezolizumab. 
Rationale 
Added for further clarification. 
Section 1.4, Synopsis, Inclusion for All Subjects, #8 
Reworded: Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in 
paraffin blocks (blocks preferred) or 10-15 at least ten 4µm and one 20µm unstained slides, 
with an associated pathology report.  This specimen will be reviewed by a central reader but 
results of review will not be required prior to registration and treatment of the subject. 
Rationale 
To ensure the correct number and types of slides are provided. 
Section 1.4, Synopsis, Inclusion for All Subjects, #8a 
Reworded: Tumor tissue has to be of good quality based on total and viable tumor content. 
Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and 
lavage samples are not acceptable. For core needle biopsy specimens, at least three cores a 
result of ten 4µm and one 20µm slides of evaluable quality have to be submitted for 
evaluation. 
Rationale 
To ensure the correct number and types of slides are provided. 
Section 1.4, Synopsis, Inclusion for All Subjects, #8c 
Reworded: Patients who do not have tissue specimens meeting eligibility requirements must 
undergo a biopsy sample collection during the screening period. Acceptable samples include 
core needle biopsies for deep tumor tissue (minimum three cores resulting in ten 4µm and 
one 20µm slides of evaluable quality) or excisional, incisional, punch, or forceps biopsy 
samples for cutaneous, subcutaneous, or mucosal lesions.

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Rationale 
To ensure the correct number and types of slides are provided. 
Section 1.4, Synopsis, Inclusion for Cohort 1, #9 
Added: Untreated with chemotherapy for metastatic disease. 
Rationale 
Added for further clarification. 
Section 1.4, Synopsis, Inclusion for Cohort 2, #12 
Changed ECOG value from ≤2 to <2. 
Rationale 
Corrected to guidelines. 
Section 1.4, Synopsis, Exclusion Criteria for ALL subjects, #2 and Section 8.2.2.2 
Prohibited Medications 
Correction of number of days to 28 days prior to Day 1 (first dose of trial product) for 
treatment with any other investigational agent or participation in another clinical trial with 
therapeutic intent. 
Rationale 
More appropriate timing. 
Section 1.4, Synopsis, Exclusion Criteria for ALL subjects, #3 
Reworded: Active central nervous system (CNS) metastases defined as computed tomography 
(CT) or magnetic resonance imaging (MRI) evaluation during screening evidence of 
progression and prior radiographic assessments or Leptomeningeal disease. 
Added: Subjects that have had prior diagnosis need to have stable disease by having 
results or performing CT/MRI with 1 month prior to first dose of treatment. 
Rationale 
To ensure exclusionary subjects are not enrolled in the trial. 
Section 1.4, Synopsis, Exclusion Criteria for ALL subjects, #4c 
Reworded: Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not currently associated 

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with spinal cord compression) could be considered for loco-regional therapy if appropriate 
prior to enrollment first dose of trial product. 
Rationale 
For clarity. 
Section 1.4, Synopsis, Exclusion Criteria for ALL subjects, #6b 
Reworded: Patients who are receiving denosumab prior to enrollment first dose of trial 
product have to be willing and eligible to receive a bisphosphonate instead while in the trial. 
Rationale 
For clarity. 
Section 1.4, Synopsis, Exclusion Criteria for ALL subjects, #11 a and b 
Clarified which subjects are allowed who have hypothyroidism and controlled Type I diabetes 
mellitus 
Rationale 
To ensure exclusionary subjects are not enrolled in the trial. 
Section 1.4, Synopsis, Exclusion Criteria for ALL subjects, #14b 
Reworded: Patients positive for HCV antibody are eligible only if polymerase chain reaction 
is negative for HCV Ribonucleic Acid (RNA) prior to enrollment first dose of trial product. 
Rationale 
For clarity. 
Section 1.5, Trial Procedure Schedule, Adverse Events 
Added collection at Screening. 
Rationale 
AEs will be collected once subject signs the informed consent. 
Section 1.5, Trial Procedure Schedule, Footnotes  
Changed numbering due to additional footnotes added. 
Section 1.5, Trial Procedure Schedule, Footnote #1 
Added footnote: ICF can be obtained prior to Screening visit. 

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Rationale 
To ensure ICF is signed prior to any protocol specific procedures are performed including 
having female subjects of child bearing potential go on adequate birth control. 
Section 1.5, Trial Procedure Schedule, Footnote #4 
Added that a follow-up visit should be scheduled if clinically indicated for follow-up on 
related SAEs/AESIs reported up to 100 days after last administration of trial product. 
Rationale 
To clarify that a follow-up visit should be scheduled if necessary, regarding the assessment of 
the SAE/AESI. 
Section 1.5, Trial Procedure Schedule, Footnote #7 
Added footnote: If there is a medical reason, subject may have MRI instead of CT scan upon 
approval from BN. 
Rationale 
To clarify that if there is a medical reason why a subject cannot have a CT scan, a MRI is 
acceptable upon approval from BN. 
Section 1.5, Trial Procedure Schedule, Footnote #9 
Added footnote: Sample collection (peripheral blood for PBMC, serum) must occur prior 
to vaccine dosing. Sample collection for Biomarker analyses should be repeated if 
subject comes off trial due to PD or AE or if the subject has an objective response. 
Rationale 
To clarify when Biomarker samples should be drawn. 
Section 1.5, Trial Procedure Schedule, Footnote #10 
Added footnote: For WOCBP, a pregnancy test is required prior to every atezolizumab infusion. 
Urine or serum pregnancy test is acceptable at any given visit depending on investigator and/or 
subject preference. 
Rationale 
To clarify that a pregnancy test is required prior to atezolizumab infusion at atezolizumab 
infusion only visits. 

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Section 1.5, Trial Procedure Schedule, Footnote #11 
Added footnote: The trial subject must be kept under close observation at the clinical 
trial site for at least 30 minutes following vaccinations. 
Rationale 
To ensure subjects are monitored after vaccine injections for safety. 
Section 1.5, Trial Procedure Schedule, Footnote #12 
Added footnote: EOT visit should take place within 28 days of withdrawal. 
Rationale 
To clarify timing of EOT visit. 
Section 2.3.2 Clinical Experience with MVA-BN and Recombinant MVA-based Vaccines 
Updated safety information.  
Rationale 
Additional information obtained since original protocol was written. 
Section 2.3.3 Safety Overview of MVA-BN and Recombinant MVA-based Vaccines, 
Serious Suspected Adverse Drug Reactions 
Updated safety information.  
Rationale 
Additional information obtained since original protocol was written. 
Section 4.1 Experimental Design 
Addition of statement regarding when a subject is considered enrolled. 
Rationale 
Since enrolled is defined differently by each Sponsor and trials, this statement was added to 
clarified what is considered enrolled in this trial. 
Section 4.1 Experimental Design and Section 9.13 Timing of Analysis 
Correction of number of subjects needed in each cohort to continue enrollment of the trial to 
Stage 2. 

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Rationale 
To match statistical considerations in the Synopsis and Section 9.7.1 Primary Efficacy 
Analysis.  These sections were written incorrectly in the original protocol. 
Section 4.1 Experimental Design and Section 9.13 Timing of Analysis 
Update to analysis population used to determine success for Stage 1, as well as how 
determination of Stage 1 success will be determined. 
Rationale 
To be conservative, the goal is to include all treated subjects in the determination of success in 
Stage 1 of the trial.  In the event that success or failure is unclear, the efficacy evaluable 
population will continue to be enrolled such that a complete determination of the success or 
failure of Stage 1 may be achieved.  Timing wording updated to correspond to the possibility 
of stopping at enrollment of the FAS, or continuing the enrollment of the EE Set in the event 
additional subjects are needed to determine Stage 1 success. 
Section 4.2.1 Screening Phase, Paragraph 3 
Addition of when the 28 day screening should be performed within, within 28 days prior to 
the first trial product. 
Rationale 
To clarify timeframe when screening assessments need to be performed. 
Section 4.2.1 Screening Phase, Paragraph 4, Bullet 6 and Section 4.2.2.2 Visit 
Description, Visits 4 and Visits 7-14 
Added: CT Scans of the thorax, abdomen and pelvis  
If there is a medical reason, subject may have MRI instead of CT scan upon 
approval from BN. 
Rationale 
To clarify that if there is a medical reason why a subject cannot have a CT scan, a MRI is 
acceptable upon approval from BN. 
Section 4.2.1 Screening Phase, Bullet List 
Added bullet: Collection of adverse events after signing of informed consent 
Rationale 
To clarify AEs are being collected after subject signs informed consent. 

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Section 4.2.1 Screening Phase, Last Paragraph  
Reworded: Women and men of reproductive potential must consent to use of highly effective 
method of contraception for the duration of the trial at least 30 days prior to first dose of 
trial product and continue for 5 months after the last dose of atezolizumab (see Appendix 1, 
Section 17.1) and the method(s) used by each subject must be documented. This list does not 
apply to subjects with same sex partners or for subjects who are and will continue to be 
abstinent from penile-vaginal intercourse on a long term and persistent basis, when this is 
their preferred and usual lifestyle. 
Rationale 
To clarify timeframe when method of contraception should start. 
Section 4.2.2.2 Visit Description, Visit 1, Visit 2 and Visit 3-14 
Addition of the following: ** The trial subject must be kept under close observation at the 
clinical trial site for at least 30 minutes following vaccination 
Rationale 
To ensure subjects are monitored after vaccine injections for safety. 
Section 4.2.5.1 Discontinuation from Treatment, Bullet #9 
The addition of: If the subject is unable or unwilling to attend all planned visits, every attempt 
should be made to perform at least a final concluding safety visit, i.e., End of Treatment 
(EOT) Visit 14/Week 100 within 28 days of withdrawal. 
If progression is observed on the CT scan scheduled per protocol or decided 
ahead of protocol-schedule for clinical reasons, CT scan does not have to be 
repeated. 
Rationale 
To clarify when the EOT visit should occur and information on CT scans. 
Section 4.2.5.1 Discontinuation from Treatment, Last Paragraph 
Addition of documenting the End of Treatment to eCRF page where subject’s unwillingness 
or unable to attend final visit needs to be documented.  
Rationale 
To specify which eCRF page to record the data. 

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Section 4.2.5.2 Discontinuation from Long Term Follow-up 
Added the following sentence: The length of the LTFU is planned to be 2 years, unless all 
subjects achieve their OS endpoint prior to the end of the 2-year period. 
Rationale 
To define length of time for long term follow-up period. 
Section 4.3 Trial Duration, Bullet 3 
Added the following:  Long Term Follow-up – Until all subjects achieve the OS endpoint, 
or a maximum time of up to 2 years. 
Rationale 
To define length of time for long term follow-up period. 
Section 4.4 Safety Monitoring Team, Paragraph 1 
Changed SMT members from Principal Investigator, the Senior Investigator, the medical 
monitor (BN) and the Director Pharmacovigilance (PV:BN) to consist of Trial Investigators, 
the medical monitor (BN) and the Director Pharmacovigilance (PV:BN). 
Rationale 
To define SMT membership. 
Section 4.5, Data and Safety Monitoring Board 
Addition of this Section. 
Rationale 
The DSMB was added at the request of IRBs. 
Renumbering of Sections 4.6 onwards due to the addition of new Section 4.5. 
Section 4.6.1 Safety Halting Rules; 8.2.7 Safety Laboratory Measurements; 9.9.1 
Adverse Events; 9.9.2 Laboratory Data and Appendix 2 
Changed NCI CTCAE from version 4.03 or newer to version 5 
Rationale 
Updated to most current version. 

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Section 6.1, MVA-BN-CV301 and 6.2, FPV-CV301 
Removed the following sentence: The specific dose will be determined upon release testing of 
the drug product. 
Rationale 
The specified dose is the nominal virus titer. 
Section 6.4, Production, Packaging and Labeling 
Added information regarding atezolizumab. 
Rationale 
Since atezolizumab is being provided by the Sponsor the information needs to be included in 
the protocol. 
Section 6.5, Shipment, Storage and Handling 
Removed the following sentence: Usage of the investigational medicinal product (IMP) is 
only allowed upon final approval of all shipment relevant paperwork by BN or its authorized 
designee.  
Rationale 
Deleted based on BNs updated SOP.  
Section 6.5, Shipment, Storage and Handling 
Added information regarding atezolizumab.  
Rationale 
Since atezolizumab is being provided by the Sponsor the information needs to be included in 
the protocol. 
Section 7.1, Collection of Blood Samples 
Added the following sentence: Sample collection must occur prior to vaccine dosing.  
Rationale 
To clarify when Biomarker samples should be drawn. 

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Section 7.2 Collection of Tumor Tissue 
Corrected the number of unstained tissue slides from 10 x 4µm and 2x 20µm sections to 
10 x 4µm and 1 x 20µm sections. 
Rationale 
Corrected to what is needed and match the Study Specific Instructions for clinical site tumor 
and biopsy samples. 
Section 7.3 Exploratory Analyses 
Added the following sentence: Tumor DNA may be analyzed for mutational burden; 
DNA damage response gene mutations, MSI status, MMR deficiency status 
Rationale 
To add additional analyses which might be performed. 
Section 8 Safety 
Added the following sentence: For the purposes of this trial, “trial vaccine” is defined as 
CV301 and “trial medication” is defined as atezolizumab. “Trial product” refers to 
both, CV301 and atezolizumab collectively. 
Rationale 
To define IMP for the purpose of the trial. 
Section 8.1.2 Adverse Events 
Added the following sentence: Clinically significant findings from the treatment period 
physical examinations will be recorded as AE. 
Rationale 
To explain what findings are reported in the eCRF. 
Section 8.1.3 Adverse Events of Special Interest (AESI), Paragraph 1 
Reworded: Autoimmune diseases and immune-mediated clinical syndromes, occurring 
emerging after signing of informed consent since the initiation of trial product, will be 
reported as potential IMAEs. 
Rationale 
To correct when AESIs will be collected. 

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Section 8.1.3 Adverse Events of Special Interest (AESI), Paragraph 4 
Appropriate management of AEs associated with immune-oncology agents, such as PD-1/L1 
blocking agents, may mitigate severe toxicity.  Management algorithms have been developed 
to assist investigators in assessing and managing the following groups of AEs: 
Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin and Neurological.  For 
details on guidelines for the management of immune related events please see the approved 
atezolizumab United States Prescribing Information (USPI) and other scientifically qualified 
guidelines (Haanen et al., 2017). 
Reworded: The use of PD-1/L1 inhibitors in cancer treatment has expanded rapidly in the last 
few years.  It is imperative that clinicians are knowledgeable about the toxicities associated 
with these agents, their recommended management and how best to monitor for them.  In 
order to increase awareness, outline strategies and offer guidance on the recommended 
management of IMAEs in subjects treated with check-point inhibitors, ASCO in collaboration 
with the National Comprehensive Cancer Network (NCCN) developed clinical practice 
guidelines (Brahmer et al., 2018) which should be referenced in addition to the mandatory 
atezolizumab United States Prescribing Information (USPI).  
Rationale 
To update guidance on AESI reporting. 
Section 8.1.3 Adverse Events of Special Interest (AESI) 
Reworded paragraph 6: AESIs should be reported on both the AE and SAE/AESI eCRF to 
BN within 24 hours of the site’s awareness.  The same timelines and reporting processes as 
for SAEs are applicable.  The collection period for AESIs begins once trial product is first 
initiated. An additional eCRF dedicated to potential IMAEs is linked to the (S)AE/AESI 
eCRF and must also be completed.  
Rationale 
To update guidance on AESI reporting. 
Section 8.1.4 Serious Adverse Events 
Added this section and moved SAE information from Section 17.3 Appendix 3 to this section. 
Rationale 
To be in line with the rest of the safety section. 
Section 8.2.2.2 Prohibited Medications 
The following paragraph was added: The following medications are prohibited during the 
trial, as well as prior to Day 1 based on the relative type of medication.  Additional 

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medications may be deemed prohibited based on review during screening, if there is the 
risk to the subject or the ability to capture the trial outcome for the subject. 
Rationale 
To provide clarification. 
Section 8.2.3 Physical Examination, Complete physical examination 
The following paragraph was added: Any clinically significant findings at the baseline 
physical examination will be recorded as medical history events, and any clinically 
significant findings post-treatment will be captured as adverse events.  The only data 
captured in the eCRF for the physical examination itself will be the date it was 
performed. 
Rationale 
To explain what findings are reported in the eCRF. 
Section 8.2.3 Physical Examination, Targeted physician examination 
The following paragraph sentence was added:  Clinically significant findings from the 
treatment period physical examinations will be recorded as AE. 
Rationale 
To explain what findings are reported in the eCRF. 
Section 8.2.5 AEs, Paragraph 1 
The following changes were made: All AEs (e.g., feeling of ill-health, subjective symptoms 
and objective signs, intercurrent diseases, accidents, etc.) observed by the investigator and/or 
reported by the subject, regardless of relationship to trial product, must be assessed and 
recorded in the AE eCRF. Only clinically significant findings from the treatment period 
physical examinations will be recorded as AE.  
Rationale 
To explain what findings are reported as AEs. 
Section 8.2.7 Safety Laboratory Measurements and Appendix 2 
Added the following table: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated. 

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Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
Rationale 
Additional grading scale to be used. 
Section 8.3.1 Reporting of SAE 
Corrected who SAE reports are to be provided to and where they are reported 
Rationale 
Align with BN SOPs. 
Section 8.3.2 Reporting of AESIs 
The addition of adding AESIs per manufacturer of Tecentriq®. 
Rationale 
The need to capture AESIs per manufacturer of Tecentriq®. 
Section 8.3.3 Reporting of Pregnancies, Paragraph 1  
Deletion of the following information: Trial product exposed pregnancies cannot be excluded 
with certainty. Subjects who are discovered to be pregnant prior to the first vaccination will 
be excluded from the trial and regarded as screen failures. Subjects who are discovered to be 
pregnant during the active trial period (up to and including 30 days after receiving a dose of 
vaccine and 5 months after receiving a dose of atezolizumab) must not receive additional 
doses of CV301 or atezolizumab, but may continue other trial procedures at the discretion of 
the investigator. All reports where the embryo or fetus may have been exposed to the trial 
product (either through maternal exposure or transmission of a investigational product via 
semen following paternal exposure) should be followed-up until delivery in order to collect 
information on the outcome of the pregnancy. 
Rationale 
Error in original protocol as this information is in regards to the reporting period for capturing 
pregnancies after completion of the trial which is stated in the next paragraph (Section 8.3.3 
Reporting of Pregnancies, Paragraph 2) 
Section 8.3.3 Reporting of Pregnancies, Paragraph 4  
Added the following information: Female subjects or female partners of male subjects will be 
counseled as to any possible known risks to either the partner or the child. At the current 
time, no pregnancies have been reported for subjects treated with CV301 and therefore 
no data exist that would identify risks to partner or child.  It is the responsibility of the 

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investigator to counsel the subject on the identified risks of atezolizumab according to 
the USPI as well as disclose any known risks prior to the subject consenting to receive 
treatment with atezolizumab. 
Rationale 
Explaining reporting procedures. 
Section 8.3.3 Reporting of Pregnancies, Paragraph 5  
Reworded: A pregnancy should be followed to term till outcome, any premature terminations 
reported, and the health status of the mother and child including date of delivery and the 
child’s gender and weight should be reported to BN as soon as possible after delivery on a 
Pregnancy Outcome Report Form (available in the Site Reference Manual). The female 
partner should sign the Pregnant Partner Informed Consent Form for follow up. 
Rationale 
Explaining reporting procedures. 
Section 9.3 Analysis Populations 
This section has been changed to make the FAS the primary analysis population for all 
analyses, and the EE Set a sensitivity population for efficacy analyses.  In addition, the 
requirements for the EE Set have been relaxed to require only both priming doses of MVA-
BN-CV301.   
Rationale 
To be conservative, and to include all treated subjects for the final analysis, the FAS is now 
used as the primary population for all analyses, including efficacy.  The EE population has 
been modified to be more inclusive such that a larger proportion of the population may be 
used for the sensitivity analyses, as well as determination of Stage 1 success. 
Section 9.4 Subject Disposition; Section 9.5 Subject Characteristics; Section 9.6 
Prior/Concomitant Medications 
Addition of FAS population. 
Rationale 
To clarify which analysis population will be presented. 
Section 9.7.1 Primary Efficacy Analysis, Paragraph 1 
Addition of the following sentence: The ORR is defined as the proportion of subjects with an 
objective tumor response (CR or PR) based on RECIST 1.1 evaluations as performed by the 

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investigator.  Based on prior published results with atezolizumab, the null ORR for 
Cohort 1 is 0.23, and for Cohort 2 is 0.15. 
Rationale 
At the request of site to include the null hypothesis in this section. 
Section 9.7.1 Primary Efficacy Analysis 
Analysis set for primary efficacy analysis changed to FAS, with EE Set now the population 
for sensitivity analyses.  Clarification added as to how the FAS and EE Set will be used to 
determine success of Stage 1. 
Rationale 
The inclusion of all treated subjects allows for a more conservative and inclusive final 
analysis.  The clarification of how to determine Stage 1 success allows the FAS population to 
be used as the primary analysis population, with allowing additional subjects to be recruited in 
the event Stage 1 success cannot be determined within the FAS set.  
Section 9.7.2.1 Progression-Free Survival 
Deletion of: Accordingly, the precise definition of progression and the timing of CT scans to 
document progression are very important. Every effort must be made to assure that 
timeframes for FU CT scans are achieved so that both treatment groups can be usefully 
compared. 
Rationale 
There will be no comparison between treatment groups. 
Section 9.7.2.1 Progression-Free Survival 
Addition of recently published meta-analysis on checkpoint inhibitor 6-month PFS rate as an 
endpoint. 
Rationale 
It complements the primary endpoint ORR in the interpretation of the trial results. 
Section 9.7.2.1 Progression-Free Survival, 9.7.2.3 Duration of Response and 9.8 
Exploratory Analysis 
Replacement EE Set with FAS 
Rationale 
FAS is the population that will be analyzed. 

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Section 9.9.1 Adverse Events 
Removal of: Similar summaries will be provided for all Grade 3 or higher TEAEs, SAEs, and 
AEs that lead to dose reduction or discontinuation of trial product. 
Rationale 
Dose reduction is not allowed. 
Section 9.10 Missing Data 
Addition of the following information: For duration of OS, PFS, or duration of response, 
subjects who are lost to FU will be analyzed as censored observations on the date of last 
known alive for OS or last radiographic assessment for PFS and duration of response.  
Missing or partial dates will be imputed for prior/concomitant medications, adverse 
events, and cancer history.  Details will be provided in the statistical analysis plan. 
Rationale 
To clarify how missing data will be handled. 
Section 9.12 Interim Analysis 
Updates to explain determination of Stage 1 success based on the update to FAS as the 
primary efficacy analysis population.  Decision tree updated to match. 
Rationale 
The primary efficacy analysis population was updated to be the FAS to be more conservative 
and inclusive.  As the determination of Stage 1 success may be unclear based on the FAS 
alone, additional enrollment of EE subjects has been explained in the event this will support 
the determination of Stage 1 success. 
Section 12.1 eCRF, Paragraph 1 
Addition of the following information: Authorized trial site personnel (i.e., listed on the 
Delegation of Authority form) will complete training based on the electronic data capture 
(EDC) system for the trial, as well as complete the trial-specific eCRFs according to the 
eCRF Completion Guidelines (provided as a separate document). 
Rationale 
Describes what training is needed for entering data into the eCRF. 
Section 12.1 eCRF, Paragraph 2 
Addition of the following information: The eCRFs exists within an EDC system with 
controlled access managed by BN or its authorized representative for this trial. Trial staff will 

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be appropriately trained in the use of trial-specific eCRFs and application of electronic 
signatures before the start of the trial, and before being given access to the EDC system. 
Original data and any changes of data will be recorded using the EDC system, with all 
changes tracked by the system and recorded in an electronic audit trial per CRF.  Note, only 
changes entered into the eCRF fields, themselves, can be used for reporting of trial 
results.  Information entered into the change logs (for example, query responses) will be 
for documenting reasons for changes only. 
Rationale 
Describes what data are used for reporting trial results. 
Appendix 4, 5, and 6  
These were renumbered to 3, 4, and 5. 
Rationale 
Due to the deletion of Appendix 3.