A Phase 2 Trial of BN-Brachyury and Radiation Therapy in Patients With Advanced Chordoma
Phase: PHASE2
Conditions: Chordoma
Sponsor: Bavarian Nordic

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Clinical Trial Protocol 
 
BRACHY-CHOR-001 
 
A Phase 2 Trial of BN-Brachyury and Radiation Therapy in 
Patients with Advanced Chordoma 
 
Version Number 4.0 
 
22-Aug-2019 
 
 
 
 
 
 
 
 
 
 
 

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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 Trial of BN-Brachyury and Radiation Therapy in Patients with Advanced 
Chordoma. 
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 current version of the Declaration of Helsinki, and applicable local 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, Independent Ethics Committee 
(IEC) review and regulatory inspections, providing direct access to source data/documents. 
 
 
 

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1.3 Responsibilities 
 
 
 
 
 
 
Title 
A Phase 2 Trial of BN-Brachyury and 
Radiation Therapy in Patients with 
Advanced Chordoma 
 
 
 
 
 
 
Principal Investigator  
 
 
 
 
 
 
 
 
 
u 
 
 
 
 
 
 
Sponsor and Product Supply  
 
Phone 
Fax 
 
 
 
 
 
 
Project Leader 
 
Phone 
 
E-mail 
 
 
 
Pharmacovigilance 
 
Phone 
 
E-mail 
 
 
 
 
 
 
Medical Monitor 
 
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 ............................................................................... 13 
1.5 Trial Procedure Schedule ................................................................. 18 
2 
Background Information and Scientific Rationale ....................... 21 
2.1 Introduction to Chordoma ............................................................... 21 
2.2 Course of Disease in Pediatric Patients versus Adults ................... 22 
2.3 Role of Radiotherapy in Treatment of Chordoma ......................... 23 
2.4 Scientific Rationale ............................................................................ 23 
2.4.1 
Identification of Brachyury as a Target Tumor Antigen .......... 23 
2.4.2 
Brachyury Expression in Chordoma .......................................... 23 
2.4.3 
Analysis of Brachyury Expression in Human Tumors and 
Normal Tissues .............................................................................. 24 
2.4.4 
Infection of Human Dendritic Cells with MVA-BN-Brachyury
 ......................................................................................................... 27 
2.4.5 
Induction of Human T Cells by MVA-BN-Brachyury .............. 29 
2.5 MVA-BN-Brachyury and FPV-Brachyury Vaccines .................... 30 
2.5.1 
Characteristics of MVA-Bavarian Nordic (MVA-BN) Vector 
and FPV Vector Backbones ......................................................... 30 
2.5.2 
Description of MVA-BN-Brachyury and FPV-Brachyury ....... 31 
2.5.3 
Previous Clinical Experience ....................................................... 32 
2.5.4 
Safety Overview of MVA-BN and Recombinant MVA-based 
Vaccines .......................................................................................... 33 
2.5.5 
Immunogenicity Overview of MVA-BN ..................................... 37 
2.5.6 
Safety Overview of Vaccinia and Fowlpox-based Vaccines 
(PROSTVAC) in Completed and Ongoing Clinical Trials ....... 38 
2.5.7 
Rationale for BN-Brachyury Prime-Boost Regimen ................. 39 

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2.5.8 
Rationale for Treatment Regimen of BN-Brachyury Plus 
Radiation ........................................................................................ 40 
2.5.9 
Trial Population ............................................................................ 41 
2.5.10 Dose Justification .......................................................................... 41 
3 
Trial Objectives ................................................................................. 42 
4 
Trial Design ....................................................................................... 43 
4.1 Experimental Design ......................................................................... 43 
4.2 Description of Trial Procedure ........................................................ 43 
4.2.1 
Screening Phase ............................................................................. 44 
4.2.1.1 
Clinical Evaluation ..................................................................... 44 
4.2.1.2 
Laboratory Studies ..................................................................... 44 
4.2.1.3 
Electrocardiogram (ECG) .......................................................... 45 
4.2.1.4 
Scans and X-Rays ........................................................................ 45 
4.2.2 
Active Trial Phase ......................................................................... 46 
4.2.2.1 
Laboratory Assessments ............................................................. 46 
4.2.2.2 
Evaluation of Response .............................................................. 46 
4.2.3 
After Treatment Completion ....................................................... 46 
4.2.4 
Unscheduled Visits ........................................................................ 47 
4.2.5 
Withdrawal from Vaccination ..................................................... 47 
4.2.6 
Premature Discontinuation .......................................................... 48 
4.3 Trial Duration .................................................................................... 48 
4.4 Data and Safety Monitoring Board (DSMB) .................................. 48 
4.5 Trial Halting Rules ............................................................................ 48 
5 
Selection of Patients .......................................................................... 49 
5.1 Recruitment Procedure ..................................................................... 49 
5.2 Inclusion Criteria .............................................................................. 49 
5.3 Exclusion Criteria .............................................................................. 49 
6 
Investigational Medicinal Product .................................................. 49 
6.1 Production, Packaging, and Labeling ............................................. 50 
6.2 Shipment, Storage, and Handling .................................................... 50 
6.3 Preparation, Administration, and Dosage ...................................... 51 
6.3.1 
Radiotherapy ................................................................................. 51 

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6.3.1.1 
Minimum Radiation Treatment Requirements ....................... 51 
6.3.1.2 
Guidelines for Radiotherapy for Definitive/Unresected 
Chordoma Treated with Curative Intent: ................................ 52 
6.3.1.3 
Treatment Planning .................................................................... 52 
6.3.1.4 
Immobilization ............................................................................ 53 
6.3.1.5 
Normal Tissue Constraints ........................................................ 53 
6.4 Accountability and Disposal ............................................................. 54 
7 
Blood Collection for Correlative Biomarker Studies (Exploratory)
 ............................................................................................................. 55 
7.1 Collection of Blood Samples ............................................................. 55 
7.2 Sample Analysis ................................................................................. 55 
7.2.1 
Analyses of PBMCs:...................................................................... 55 
7.2.2 
Analyses of Serum ......................................................................... 55 
7.2.3 
Collection, Processing, and Testing of Biomarker Samples ...... 55 
7.3 Future Use of Lab Specimens ........................................................... 56 
8 
Safety .................................................................................................. 56 
8.1 Definitions .......................................................................................... 56 
8.1.1 
Adverse Event ................................................................................ 56 
8.1.2 
Suspected Adverse Reaction ........................................................ 57 
8.1.3 
Unexpected Adverse Reaction ..................................................... 57 
8.1.4 
Serious Adverse Event (SAE) ...................................................... 57 
8.1.5 
Adverse Event of Special Interest ................................................ 58 
8.1.6 
Unanticipated Problem ................................................................. 58 
9 
Assessments and Trial Procedures .................................................. 59 
9.1 Medical History ................................................................................. 59 
9.2 Prior and Concomitant Medication ................................................. 59 
9.3 Physical Examination and Medical Assessment ............................. 60 
9.3.1 
Safety Laboratory Measurements ............................................... 60 
9.4 CT Scan .............................................................................................. 61 
9.5 Reporting ............................................................................................ 61 
9.5.1 
Collecting and Recording Adverse Events ................................. 61 
9.5.2 
Reporting of SAEs ......................................................................... 62 

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9.5.3 
Reporting of AESIs ....................................................................... 63 
9.5.4 
Reporting of Pregnancies ............................................................. 63 
9.5.5 
Progression of Underlying Malignancy ...................................... 64 
10 
Statistical Considerations ................................................................. 64 
10.1 Primary Trial Hypothesis ................................................................. 64 
10.2 Endpoints ........................................................................................... 64 
10.3 Sample Size Consideration ............................................................... 65 
10.4 Trial Cohort/ Data Set to be Evaluated ........................................... 65 
10.4.1 Analysis Sets .................................................................................. 65 
10.4.2 Analysis Periods ............................................................................ 66 
10.4.3 Timing of Analysis ........................................................................ 66 
10.4.4 Subgroup Analysis ........................................................................ 67 
10.4.5 Efficacy Analysis ........................................................................... 67 
10.4.5.1 Primary Efficacy Analysis .......................................................... 67 
10.4.5.2 Secondary Efficacy Analysis ...................................................... 67 
10.4.5.3 Exploratory Analyses ................................................................. 68 
10.4.6 Safety Analysis ............................................................................... 69 
10.5 Response Criteria .............................................................................. 69 
10.6 Toxicity Criteria ................................................................................ 70 
11 
Ethical Aspects .................................................................................. 70 
11.1 Ethical and Legal Regulations ......................................................... 70 
11.2 Approval by an Institutional Review Board / Independent Ethics 
Committee .......................................................................................... 71 
11.3 Confidentiality and Data Protection ................................................ 71 
12 
Informed Consent and Assent ......................................................... 72 
13 
eCRF and Retention of Records ...................................................... 73 
13.1 Electronic Case Report Form (eCRF) ............................................. 73 
13.2 Retention of Records ......................................................................... 73 
13.3 Protocol Deviations............................................................................ 74 
14 
Monitoring of the Trial ..................................................................... 74 
15 
Audits and Inspections ..................................................................... 75 
16 
Responsibility of the Investigator .................................................... 75 

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17 
References .......................................................................................... 77 
Appendix 1: RECIST 1.1 Criteria ........................................................... 83 
Confirmation .............................................................................................. 83 
Duration of Overall Response ................................................................... 84 
Measurable Disease .................................................................................... 84 
Malignant Lymph Nodes ........................................................................... 84 
Non-Measurable Disease ........................................................................... 84 
Evaluable Disease ....................................................................................... 85 
Target Lesions ............................................................................................ 85 
Non-Target Lesions .................................................................................... 85 
Appendix 2: Eastern Cooperative Oncology Group Performance 
Status .................................................................................................. 86 
 
 

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List of Tables 
Table 1 
Summary of Systemic Therapy Data (Heery, 2016) ............................21 
Table 2 
Brachyury Protein Expression Analyzed by IHC ................................24 
Table 3 
Brachyury Expression Analyzed by Brachyury-specific Monoclonal 
Antibody and/or PCR .............................................................................26 
Table 4 
In vitro Infection of Human DCs with MVA-BN-Brachyury .............27 
Table 5 
Summary of Suspected ADRs Reported by ≥ 1% in Vaccinia-Naïve 
vs. Vaccinia-Experienced Populations in Completed MVA-BN 
Clinical Trials* ........................................................................................33 
Table 6 
Serious Suspected Adverse Drug Reactions (Assessed by the 
Investigator to be at Least Possibly Related to MVA-BN) .................36 
Table 7 
ADRs for FPV (Originating from PROSTVAC Program) .................39 
Table 8 
Normal Tissue Radiation Dose Constraints .........................................53 
 
 
List of Figures 
Figure 1 
Tissue Sections Stained for Brachyury Expression .............................25 
Figure 2 
Detection of Brachyury Expression by Western Blot Analysis ..........28 
Figure 3 
Detection of Brachyury by Immunofluorescence ................................28 
Figure 4 
Brachyury-specific CD8+ T cell Stimulation by MVA-BN-Brachyury-
infected DCs Compared with MVA-TRICOM-infected DCs .............29 
Figure 5 
MVA-BN-Brachyury (and not MVA-WT)-infected Human DCs 
Expand CD4+ T cells from PBMCs of Normal Donors that Recognize 
Purified Brachyury Protein ...................................................................30 
Figure 6 
Lysis of UCH-1 Cells by Brachyury-specific T Cells ...........................40 
Figure 7 
Trial Vaccine Schedule ...........................................................................44 
 
 
 
 

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List of Abbreviations 
Abbreviations  
Definitions  
Ab 
Antibody 
Abcam 
monoclonal anti-Brachyury antibody 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase  
BPI-SF 
Brief Pain Inventory (Short Form) 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical Target Volume 
DC 
Dendritic Cells 
DL 
Dose Level 
DSMB 
Data and Safety Monitoring Board 
DVH 
Dose Volume Histograms 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ELISA 
Enzyme-linked Immunosorbent Assay 
FAS 
Full analysis set 
FOCBP 
Females of child-bearing potential 
FPV 
Fowlpox virus 
GCP 
Good Clinical Practice 
GyRBE 
Gray relative biological effectiveness 
GM-CSF 
Granulocyte Macrophage Colony-Stimulating Factor 
GTV 
Gross Target Volume 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus  
HCG 
Human Chorionic Gonadotropin 
HSA 
Human Serum Albumin 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee  
IFN 
type I interferon 
IHC 
Immunohistochemistry 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IV 
Intravenous 
LTIB 
Laboratory of Tumor Immunology and Biology 
MOI 
Multiplicity of Infection 
MRI 
Magnetic resonance imaging 
MVA-WT 
wild-type MVA 
NCI 
National Cancer Institute 

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Abbreviations  
Definitions  
NK 
Natural Killer 
ORR 
Objective Radiographic Response Rate 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
progressive disease 
PFS 
Progression Free Survival 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PR 
Partial Response 
PRNT 
Plaque Reduction Neutralization Test 
PTV 
Planning Target Volume 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors 1.1 
RT-PCR 
Reverse-Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SBRT 
Stereotactic Body Radiotherapy 
SC 
subcutaneously 
TAA 
Tumor Associated Antigen 
TBNK 
T-cell, B-cell, and Natural Killer Cell Quantitation by Flow 
Cytometry/Lymphocyte surface marker analysis 
TEAE 
Treatment-Emergent Adverse Events 
TRICOM 
TRIad of COstimulatory Molecules 
TSH 
Thyroid stimulating hormone 
 
 

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1.4 Protocol Synopsis 
Title 
 A Phase 2 Trial of BN-Brachyury and Radiation Therapy in 
Patients with Advanced Chordoma 
 
  
Clinical phase 
 Phase 2 
 
  
 
Sponsor 
  
Bavarian Nordic A/S 
 
  
 
Principal 
Investigator 
 
 
Number of sites 
  
Minimum 4, Up to 10 (USA) 
 
 
  
Vaccination dose, 
schedule and 
administration route  
 
 
Prime with Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN)-
Brachyury given subcutaneously (SC) for one dose each on Day 0 and 
Day 14. Administer each dose as four separate 0.5 mL injections (for a 
total dose of at least 5 x 107 Inf.U) one in each arm, one in each leg 
using professional standards and practices.  
 
Boost with Fowlpox Virus (FPV) -Brachyury given SC on Day 28, 
then every 4 weeks for 4 doses (End of Radiation +2, 6, 10, and 
14 weeks), then given every 12 weeks (End of Radiation +26, 38, 50, 
62, 74, 86, 98, and 110 weeks). One dose = one 0.5 mL injection with a 
nominal titer of 1 x 109 Inf.U per 0.5 mL.  
 
  
 
Trial duration 
 
 The total duration of the trial for each patient is up to 29 months 
 
Trial population 
 Patients at least 12 years old with advanced chordoma who are planning 
to be treated with radiotherapy to at least one lesion. Patients will have 
no history of autoimmune disease (with exceptions detailed in the 
exclusion criteria below), will have measurable disease as defined by 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and will 
have adequate organ function 
 
  
Number of patients 
 Planned trial size is based on a Simon 2-stage design, in which 10 
patients are treated initially. If ≥1 patient(s) in the first 10 have an 
objective response [partial response (PR) or complete response (CR)] 
by RECIST 1.1, an additional 19 patients may be enrolled for a total of 
29 patients. Otherwise, the trial will be stopped. If 4 or more objective 
responses are observed in 29 patients, the null hypothesis that the true 
Objective Radiographic Response Rate (ORR) anytime within 12 
months post completion of radiation is 5% or less will be rejected. This 

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design yields a one-sided type I error rate of 5% and power of 80% 
when the true response rate is 20%. 
 
  
Primary objectives 
 
To determine if the combination of BN-Brachyury administered with 
radiotherapy will result in a clinically meaningful ORR when 
compared with historical control. 
 
  
Secondary objectives  • 
To confirm the safety profile of BN-Brachyury plus radiation 
therapy 
• 
Progression Free Survival (PFS) by modified RECIST 1.1 
criterion 
• 
Improvement in clinical symptoms as measured by the Brief Pain 
Inventory (Short Form) [BPI-SF] pain assessment 
Exploratory 
objectives 
 • 
Evaluate the differences in clinical outcome measures by location 
of primary tumor (Sacral vs. Mobile Spine vs. Clival) 
• 
Measure adverse event profile by location of primary tumor 
• 
To evaluate other clinical endpoints that might be indicative of 
clinical benefit: 
o ORR by standard RECIST 1.1 
o PFS by other criteria [Choi (Choi, 2007), volumetric (Fenerty 
et al., 2016), standard RECIST 1.1]  
• 
To evaluate changes in immune and tumor related biomarkers of 
pre- versus post-baseline samples  
o Peripheral blood mononuclear cells (PBMC) 
▪ Brachyury and other Tumor associated antigen 
(TAA) specific T cell activation  
▪ Immune 
cell 
subset 
quantification 
and 
characterization  
o Serum  
▪ Analysis for soluble factors associated to immune 
response e.g. antibodies or cytokines 
 
Primary endpoints 
 ORR anytime within 12 months post completion of radiation on target 
lesion(s) based on modified RECIST 1.1. Refer to Section 10.5 for the 
response criteria. 
 
  
Secondary efficacy 
endpoints 
 
 • 
PFS by modified RECIST 1.1 
• 
Improvement in clinical symptoms measured by the BPI-SF 
Safety endpoints 
 
 
 • 
Injection site reaction 
• 
Other adverse events 
• 
Clinically significant shifts in chemistry and hematology 
laboratory values 
 
 
 
 

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Exploratory 
endpoints 
 • 
ORR anytime post completion of radiation on all lesions by 
standard RECIST 1.1 
• 
ORR anytime within 12 months post completion of radiation on 
target lesion(s) based on Choi (Choi, 2007) criteria and 
volumetric criteria 
• 
PFS based on all lesions by standard RECIST 1.1 
• 
PFS based on target lesion(s) by Choi (Choi, 2007) criteria and 
volumetric criteria 
 
Trial design 
 This is a single arm Phase 2 clinical trial using a Simon 2-stage optimal 
design. The goal is to demonstrate that BN-Brachyury plus radiation 
therapy can induce objective radiographic responses in patients. In 
stage 1, a minimum threshold of activity will be needed to proceed to 
stage 2.  
 
  
Inclusion criteria 
 1. Diagnosis:  Patients must have histologically confirmed chordoma 
by the pathology department of the site to enroll the patient on trial, 
which is metastatic or unresectable locally advanced. Patients with 
potentially curable disease are eligible if the patient refuses therapy 
with curative intent and all other eligibility criteria are met.   
2. Patients must have measurable disease by RECIST 1.1  
(Appendix 1). 
3. Patient must be scheduled to have radiation therapy to at least 
1 target lesion with a minimum biologic equivalence of 8Gy in 
1 fraction (see Section 6.3.1.1 for equivalent doses). Any lesion 
irradiated within the previous 1 year cannot be a RECIST 1.1 target 
lesion. 
4. Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 to 2 at trial entry (See Appendix 2).  
5. Age ≥ 12 years.   
6. Patients must have normal organ and marrow function as defined 
below: 
a. Serum creatinine  1.5 x upper limit of normal OR 
creatinine clearance on a 24-h urine collection of  
60 mL/min. 
b. Alanine Aminotransferase (ALT) and Aspartate 
Aminotransferase (AST)  2.5 x the upper limit of normal. 
c. Total bilirubin ≤ 1.5 x upper limit of normal OR in patients 
with Gilbert’s syndrome, a total bilirubin  3.0 x upper limit 
of normal. 
d. Hematological eligibility parameters (within16 days of 
initiating treatment):  
i. Granulocyte count  1,500/mm3 
ii. Platelet count 100,000/mm3 
iii. Resting Pulse oximetry > 90% on room air. 
7. Must have recovered completely (Grade 1, stable, baseline) from 
any reversible toxicity associated with recent therapy. Typically, 

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this is 3–4 weeks for patients who most recently received cytotoxic 
therapy, except for the nitrosoureas and mitomycin C for which 
6 weeks is needed for recovery.   
8. There should be a minimum of 2 weeks from any chemotherapy, 
small molecule/targeted therapy, immunotherapy and/or radiation 
prior to start of trial treatment. 
9. Females of child-bearing potential (FOCBP) and male partners of 
FOCBP must agree to use effective birth control or abstinence from 
screening up to and including the day of the last vaccination 
therapy.  
10. Ability to understand and the willingness to sign a written informed 
consent or in the case of ages 12 to 17, an assent document. 
 
Exclusion criteria 
 Patients with any of the following will not be eligible for participation 
in this trial: 
1. Concurrent systemic treatment for cancer. 
2. Patients with rapidly progressing disease at multiple sites 
3. Patients with poorly differentiated or dedifferentiated chordomas 
4. Chronic hepatitis B or C infection, because potential immune 
impairment caused by these disorders may diminish the 
effectiveness of this immunologic therapy. 
5. Any significant disease that, in the opinion of the investigator, may 
impair the patient’s tolerance of trial treatment.  
6. Significant dementia altered mental status, or any psychiatric 
condition that would prohibit the understanding or rendering of 
informed consent. 
7. Active autoimmune diseases requiring treatment or a history of 
autoimmune disease that might be stimulated by vaccine treatment. 
This requirement is due to the potential risks of exacerbating 
autoimmunity. However, patients with vitiligo or clinically stable 
autoimmune endocrine disease (i.e.: Hashimoto’s thyroiditis) who 
are on appropriate replacement therapy (if such therapy is 
indicated) are eligible.  
8. Concurrent use of systemic steroids, except for physiologic doses 
of systemic steroid replacement or local (topical, ophthalmic, nasal, 
or inhaled) steroid use. Limited pharmacologic doses of systemic 
steroids (e.g., in patients with exacerbations of reactive airway 
disease or to prevent intravenous (IV) contrast allergic reaction or 
anaphylaxis in patients who have known contrast allergies) are 
allowed. 
9. Patients who are receiving any other investigational agents within 
28 days before start of trial treatment. 
10. History of allergic reactions attributed to compounds of similar 
chemical or biologic composition to MVA-BN ®/FPV-Brachyury 
or other agents used in trial. History of allergic reaction to 
aminoglycoside antibiotics or egg products. 
11. Serious or uncontrolled intercurrent illness including, but not 
limited to, ongoing or active infection, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or 

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psychiatric illness/social situations that, in the opinion of the 
investigator, would limit compliance with trial requirements. 
12. Pregnant women are excluded from this trial due to the unknown 
effects of the BN-Brachyury on the fetus or infant. Because there is 
an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with BN-Brachyury, 
breastfeeding should be discontinued if the mother is treated with 
BN-Brachyury. These potential risks may also apply to other agents 
used in this trial. 
13. Human immunodeficiency virus (HIV)-positive patients are 
ineligible because of the potential for decreased immune response 
to the vaccine. 
14. Significant cardiovascular disease, which includes but is not limited 
to New York Heart Association 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. 
 
  

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1.5 Trial Procedure Schedule 
 
Screening/ 
Baseline 
Day 0 
Day 14 
Day 28 
Day 42-70 
(approximate) 
End Radiation11 
+ 2 weeks 
End Radiation  
+ 6 weeks 
End Radiation 
 + 10 weeks 
End Radiation   + 
14 weeks 
End Radiation + 
26 weeks 
End Radiation + 
38, 50, 62, 74, 86, 
98, 110 weeks12  
Post-treatment 
follow-up  
+30 days after 
last Treatment 
visit 
Visit Window 
 
 
±2 days 
±2 days 
 
+7days 
-4/+7days 
-4/+7days 
-4/+7days 
±2 weeks 
±2 weeks 
±2 days 
History and physical 
examination1 
X 
 
 
 
 
 
 
 
 
 
 
X 
Medical assessments2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum HIV antibody3 
X 
 
 
 
 
 
 
 
 
 
 
Serum hepatitis B & C4 
X 
 
 
 
 
 
 
 
 
 
 
CBC with differential, platelet 
count 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry5 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Beta-HCG6 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TBNK 
X 
 
 
X 
 
X 
X 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
CT and MRI7 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Correlative biomarker studies 
(blood)8 
X 
 
 
X 
 
X 
X 
 
 
 
 
Pulse oximetry 
X 
 
 
 
 
 
 
 
 
 
 
MVA-BN-Brachyury  
 
X 
X 
 
 
 
 
 
 
 
 
FPV-Brachyury 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 

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Screening/ 
Baseline 
Day 0 
Day 14 
Day 28 
Day 42-70 
(approximate) 
End Radiation11 
+ 2 weeks 
End Radiation  
+ 6 weeks 
End Radiation 
 + 10 weeks 
End Radiation   + 
14 weeks 
End Radiation + 
26 weeks 
End Radiation + 
38, 50, 62, 74, 86, 
98, 110 weeks12  
Post-treatment 
follow-up  
+30 days after 
last Treatment 
visit 
Visit Window 
 
 
±2 days 
±2 days 
 
+7days 
-4/+7days 
-4/+7days 
-4/+7days 
±2 weeks 
±2 weeks 
±2 days 
Radiotherapy9 
 
 
 
 
X 
 
 
 
 
 
 
RECIST-based Assessment10 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPI-SF 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1Baseline: History and physical and laboratory studies should be completed within 16 days of initiating treatment. Baseline radiographic and immunologic 
studies should be obtained within 28 days of initiating treatment. History and physical includes all components of medical assessments. Special attention should 
be paid to any history of vaccine allergies.  
2Medical assessments include a complete neurologic examination including documentation of cranial nerve, motor, sensory, cerebellar, and deep tendon reflex 
examinations; interim history (since last visit); vital signs; physical examination (at baseline); targeted physical exam (Day 0-28, End of Radiation +2-+110 
weeks, and Post-treatment follow up visits) and ECOG performance status. To be performed within 3 days prior of each dose of vaccine. Repeat medical 
assessment is not required at baseline if history and physical has been performed within 3 days of vaccine administration on day 0. 
3Serum HIV antibody should be completed within 6 months of initiating treatment. 
4Serum hepatitis B & C antibody should be completed within 6 months of initiating treatment. 
5Chemistry panel: Na+, K+, Cl–, CO2, glucose, (BUN), creatinine, albumin, alkaline phosphatase, ALT, AST, total bilirubin, thyroid stimulating hormone 
(TSH), calcium, and ANA to be performed within 16 days prior to screening/ baseline per protocol. TSH is optional after screening visit.  
6In females of child-bearing potential, Beta-HCG to be done at baseline 48 hours prior to treatment and within 48 hours of any dose of vaccine or radiation. 
7CT chest, abdomen, and pelvis and MRI (if target lesion is best visualized by MRI)  
8Correlative biomarker studies (blood): 6 (10 mL) green top sodium heparin tubes for PBMC; 1 (8.5 mL) SST tubes for serum samples. 
9Radiotherapy schedule and dose selected by treating radiation oncologist. Radiotherapy will begin at least 2 weeks and ideally not more than 4 weeks after first 
administration of FPV-Brachyury (Dose 3).  

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10 RECIST based assessment includes using RECIST principles (see Section 10.5) to measure the “target” lesions, defined as those meeting RECIST 
requirements for measurability and those that will be treated with radiation as defined by minimum requirements of the protocol. “Non-target” lesions may 
include those that are not measurable by RECIST or those that are measurable and not treated with radiotherapy at the dose required by protocol (per Section 
6.3.1).  
11Time noted is from end of radiation or until resolution of AEs related to radiation, whichever is later 
12Vaccine doses will be administered in 12 week intervals through approximately 2 years of post-radiation treatment see Figure 7. 
 
 

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2 Background Information and Scientific Rationale 
2.1 Introduction to Chordoma 
Chordoma is a rare tumor occurring in the bones of the skull and spine and is a type of sarcoma. 
Chordoma tumor cells arise from the remnant notochord; the notochord is present in the 
developing embryo and is replaced by the spine in fetal development. Most chordomas develop 
sporadically. The mechanism by which chordomas arise is not yet completely clear and may be 
related to development of mutations or inappropriate epigenetic control of normal genes, with 
only a very small fraction of chordomas being hereditary (Yang et al., 2005). Notably, the 
hereditary cases of chordoma have been linked to a single nucleotide polymorphism in the 
T gene, which encodes the transcription factor Brachyury, not a germline mutation (Bettegowda 
et al., 2017). Brachyury is important in the development of the notochord, is highly expressed in 
chordomas, and appears to be an oncogenic driver of the disease (Nibu et al., 2013, Vujovic et al., 
2006). 
Chordomas are described by the location of the primary tumor (sacrum, mobile spine, and clivus) 
and how they appear under a microscope (conventional, poorly differentiated, dedifferentiated 
and chondroid). Symptoms depend on the location and size of the tumor, and the diagnosis is 
based on characteristic radiologic and pathologic findings (Heery, 2016). 
Treatment for chordoma usually involves surgery to remove as much of the tumor as possible 
depending on the location and is often performed in conjunction with high doses of radiation 
therapy (Stacchiotti et al., 2015). Recurrence is common and may require multiple surgeries 
and/or radiation depending on the location. For patients with advanced or inoperable disease, 
chemotherapy and targeted therapies have failed to have a clear impact on the disease course in 
clinical trials, despite rare case reports of responses to some chemotherapy and targeted therapy 
agents (refer to Table 1)(Heery, 2016). Currently, there are no drugs approved by the FDA for 
treating chordoma. The prognosis is dependent on different factors including the patient’s age, 
type of chordoma, size and location of tumor, method of treatment, extent of resection, and other 
factors, but few patients with chordoma are cured with an estimated 6-7 year median overall 
survival (McMaster et al., 2001). Therefore, additional therapies for the treatment of chordoma 
are needed.  
Table 1 
Summary of Systemic Therapy Data (Heery, 2016) 
Therapy 
Target 
Number of 
Chordoma 
Patients 
Reported Results 
Trial Design 
References 
Imatinib 
PDGFR 
50 
1 PR (RECIST); 35 
SD; median PFS = 9 
months (RECIST) 
Single-arm 
Phase 2 trial 
Stacchiotti, 
2012 
Imatinib 
PDGFR 
17 
0 PR; 17 SD 
Case series 
Ferraresi, 
2010 

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Therapy 
Target 
Number of 
Chordoma 
Patients 
Reported Results 
Trial Design 
References 
Lapatinib 
EGFR 
18 
13 SD; 6 PR (Choi); 0 
PR (RECIST); median 
PFS = 8 months 
(RECIST) 
Single-arm 
Phase 2 trial 
Shalaby, 2011 
Erlotinib 
EGFR 
1 
1 PR 
Case report 
Singhal, 2009 
Erlotinib + 
bevacizumab 
EGFR, VEGF 
3 
3 SD 
Case report 
Asklund, 
2014 
Cetuximab + 
gefitinib 
EGFR 
1 
1 PR 
Case report 
Hof, 2006 
Cetuximab + 
gefitinib 
EGFR 
1 
1 PR 
Case report 
Linden, 2009 
Sorafenib 
Multiple 
27 
1 PR (RECIST); 
9-month PFS = 
73.0%; 12-month OS 
= 86.5% 
Single-arm 
Phase 2 trial 
Bompas, 2015 
9-Nitro-
camptothecin 
Topoisomerase 
1 
15 
1 PR (RECIST); 
median PFS = 9.9 
months 
Single-arm 
Phase 2 trial 
Wilhelm, 
2008 
Thalidomide 
Multiple 
1 
1 PR 
Case report 
Chay, 2011 
GI-6301 
(recombinant 
yeast-Brachyury 
vaccine) 
Brachyury 
11 
1 PR (RECIST); 
1 mixed response 
(RECIST); median 
PFS = 8.3 months 
Phase 1 trial 
Heery, 2015 
PR – partial response; PFS – progression free survival; RECIST – Response Evaluation Criteria in Solid Tumors; 
SD – stable disease 
Adapted from Heery (2016).  
2.2 Course of Disease in Pediatric Patients versus Adults 
As reported by Beccaria (Beccaria et al., 2015), chordomas occur in less than 1/1,000,000 of the 
population, with incidence peaking between the fourth and sixth decades. Less than 5% of 
chordomas present in the first two decades, with the average age of ~10 years in children 
diagnosed with chordoma.  
Chordoma in children and adults primarily occurs in different locations. Chordoma is 
predominantly found in the sacro-coccygeal region in adults and in the intracranial region in 
children (Beccaria et al., 2015). In pediatric populations, intracranial tumors are considered to 
have a better outcome than chordoma found in the sacro-coccygeal region (Ridenour et al., 2010, 
Benk et al., 1995, Coffin et al., 1993). Children have better overall survival rates at five years 
compared with adults, reported as 56.8 to 81% vs. 23 to 66% in adults (O'Connell et al., 1994, 
Mitchell et al., 1993). However, children under the age of five years are more prone to aggressive 
tumors and a worse prognosis (Borba et al., 1996). Based on the literature reviewed here, it 
appears that adolescent patients with chordoma more closely approximate the outcomes in adults 
than children under the age of five. 

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2.3 Role of Radiotherapy in Treatment of Chordoma 
Radiotherapy is a core treatment modality for the management of chordoma. Radiotherapy 
appears to play a critical role in the local recurrence rate after surgical resection (DeLaney et al., 
2009, Chen et al., 2013, Park et al., 2006). Despite the apparent ability of high dose radiation to 
prevent recurrence in historical (uncontrolled) case series, the effects on established chordoma 
tumors is less readily measured. In fact, an analysis of chordoma cases treated with high dose 
radiotherapy found less than 5% of all patients had objective responses by RECIST (>30% 
decrease in sum of single axes). At 12 months, none of the patients had achieved objective 
response. Only at about 18 months had any patients reached the 30% tumor size reduction 
required for a response, and those were still a small minority of cases (<5%) (Kabolizadeh et al., 
2017). Based on these findings, it appears we can confidently state that the expected historical 
response rate with radiotherapy alone in chordoma is 0-5% at 1 year. 
2.4 Scientific Rationale 
2.4.1 Identification of Brachyury as a Target Tumor Antigen 
Using a computer-based differential display analysis tool to conduct global comparison of 
expressed sequence tag clusters in the Unigene database (Baranova et al., 2001, Krukovskaja et 
al., 2005), the gene encoding for the transcription factor Brachyury was identified as highly 
represented in tumor-derived libraries and rarely observed in normal tissue-derived libraries 
(Palena et al., 2007). Brachyury is a member of the T-box family of transcription factors, 
characterized by a highly conserved DNA-binding domain designated as T-domain (Herrmann et 
al., 1990, Edwards et al., 1996, Kispert et al., 1995, Kispert and Hermann, 1993). Brachyury 
homologs have been reported to be involved in embryonic mesodermal development (Herrmann 
et al., 1990, Kispert et al., 1994, Wilkinson et al., 1990, Schulte-Merker and Smith, 1995, 
Yamaguchi et al., 1999) and this will be discussed in more detail below.   
2.4.2 Brachyury Expression in Chordoma 
Chordoma cells are identified and differentiated from other similar appearing tumor cells based 
on the expression of Brachyury (Tirabosco et al., 2008, Miettinen et al., 2015). Brachyury 
expression in chordoma is not only nearly universally present; it appears to be an oncogenic 
driver of the disease (Tirabosco et al., 2008, Miettinen et al., 2015). Ongoing work has focused 
on controlling Brachyury to limit chordoma cell growth and survival. An alternative approach is 
to target Brachyury immunologically. Because of its universal expression, it is unlikely that 
downregulation of Brachyury as a mechanism of resistance is possible because downregulation 
would make the tumor cells less tumor-like in nature. 
Chordomas are known to overexpress Brachyury, a transcription factor present in the notochord 
during development (Tirabosco et al., 2008, Miettinen et al., 2015, Vujovic et al., 2006). 
Expression of Brachyury by chordoma cells has been identified as a potential target for treatment 

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of chordoma, but molecular therapies have proven incapable of targeting transcription factors 
effectively.   
2.4.3 Analysis of Brachyury Expression in Human Tumors and Normal Tissues 
RT-PCR: By using reverse-transcription followed by polymerase chain reaction (RT-PCR), 
investigators in the Laboratory of Tumor Immunology and Biology (LTIB) have identified the 
over-expression of Brachyury in gastrointestinal, bladder, kidney, ovary, uterus, and testicular 
carcinomas. Similar studies also found over expression of Brachyury mRNA in cell lines of lung, 
colon and prostate cancers, but not in the majority of normal tissues tested, with the exception of 
expression in the testis, thyroid and low levels of expression in B cells pooled from multiple 
normal donors (see detailed analysis below).   
Immunohistochemistry (IHC): IHC analysis of Brachyury expression using an anti-Brachyury 
monoclonal antibody (Ab) confirmed the tumor specificity of this transcription factor. Expression 
of Brachyury was found in approximately 40% of primary lung tumor tissues, including 
adenocarcinoma (48% positive), squamous carcinoma (25% positive) and others (50% positive) 
(Table 2, Figure 1A-D). Over-expression of Brachyury was also observed by IHC analysis in 
breast primary tumor tissues and metastatic lesions.  Brachyury was expressed by 16 of 20 
primary tumor samples (80%) of infiltrating ductal adenocarcinomas.  Moreover, Brachyury was 
highly expressed in 8 out of 8 metastatic lesions of breast cancer, obtained from lymph nodes (4), 
pleura (1), bone (2), and brain (1) (Figure 1E).    
Table 2 
Brachyury Protein Expression Analyzed by IHC 
Lung tumor tissues 
Brachyury positive 
Adenocarcinoma 
10/21 (48%) 
Squamous Carcinoma 
3/12 (25%) 
Undifferentiated Carcinoma 
2/4 (50%) 
Bronchioalveolar 
1/1 (100%) 
Small Cell Lung Cancer 
0/1 (0%) 
Total 
16/39 (41%) 
Roselli et al. (2012) 

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Figure 1 
Tissue Sections Stained for Brachyury Expression 
 
 
Roselli et al. (2012), NCI Internal Data   
Stains corresponding to a lung adenocarcinoma (A); a squamous carcinoma (B); and a bronchioalveolar carcinoma, 
mucinous type (C). Lung tumor cells invading a blood vessel, positive for Brachyury expression (D). IHC staining 
for Brachyury in a bone metastasis of breast cancer (E). 
IHC analysis of normal tissues obtained from non-cancer patients demonstrated Brachyury 
expression in: 0/5 lung, 0/3 heart, 0/3 brain, 0/3 liver, 0/3 kidney, 0/3 spleen, 0/3 skeletal muscle, 
0/1 adrenal gland, 0/1 skin, 4/6 thyroid, and 3/3 testis analyzed (Table 3). 
A 
B 
C 
E 

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Table 3 
Brachyury Expression Analyzed by Brachyury-specific Monoclonal Antibody 
and/or PCR 
Normal Human Tissues Negative for Brachyury Expression 
Adrenal 
Liver 
Blood Cells 
Lung 
Bone Marrow 
Lymph Node 
Breast 
Ovary 
Cerebellum 
Pancreas 
Cerebral Cortex 
Placenta 
Colon 
Prostate 
Endothelium 
Skin 
Gastrointestinal Tract 
Spleen 
Heart 
Striated Muscle 
Kidney (glomerulus, tubule) 
Thymus 
Normal Human Tissues Positive for Brachyury Expression 
Testes (3/3) 
 
Thyroid (4/6) 
 
Hamilton et al. (2012) 
Detailed Analysis of Normal Human Tissues Expressing Brachyury: The expression of 
Brachyury mRNA in normal B cells was further evaluated in CD19+ B cell fractions isolated 
from various healthy donors; weak amplification was observed in 4/9 samples analyzed by 
RT-PCR. These results at the RNA level, however, contrasted with data obtained by 
immunohistochemistry analysis in normal spleens and lymph nodes, which resulted negative for 
the expression of Brachyury protein (Table 3). Moreover, the cytotoxic lysis of normal B cells 
was evaluated by using Brachyury-specific T cells as effectors; no lysis was observed with any of 
the normal B cells purified from the blood of five different healthy donors (Palena et al., 2007). 
The LTIB have determined that Epstein - Barr virus infection of human B cells enhances 
Brachyury expression; approximately 1 in 105-106 human B cells have latent Epstein - Barr virus 
infection.  
There was expression of Brachyury in testis (3 of 3 positive) (Table 3). However, due to the 
blood-testis barrier, a paucity of antigen presenting cells within the testis and a lack of major 
histocompatibility complex molecules on testicular cells, proteins expressed within the testis are 
considered immune privileged (Fijak and Meinhardt, 2006). Cancer testis antigens form a class of 
proteins expressed on tumor cells and the testis and multiple vaccines have been generated 
against these antigens without immune related adverse events within the testis. 
The expression of Brachyury protein was also detected in 3 of 4 thyroid tissue lysates evaluated 
by Western Blot. These results at the protein level contrasted with the expression of Brachyury at 
the mRNA level which was negative in 3/3 individual thyroid tissues tested by RT-PCR. 
Altogether, these results indicate Brachyury expression in 7/13 thyroid tissues analyzed.     

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2.4.4 Infection of Human Dendritic Cells with MVA-BN-Brachyury 
MVA-BN-Brachyury [also referred to as MVA-Brachyury-TRICOM (TRIad of COstimulatory 
Molecules); refer to Section 2.5 for a description] was investigated in numerous in vitro studies. 
In order to investigate the ability of MVA-BN-Brachyury to infect cells from the blood of normal 
donors, dendritic cells (DCs) were prepared from PBMCs by culture for 6 days in the presence of 
Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) and IL-4, and subsequently 
incubated with wild-type MVA (MVA-WT), MVA-TRICOM (expressing only the 3 
costimulatory molecules), or MVA-BN-Brachyury.  
Using MVA-WT alone, no increased expression of CD80, CD54, or CD58 was observed. 
MVA-TRICOM resulted in upregulation of each of the 3 costimulatory molecules. Addition of 
the target antigen, Brachyury, did not interfere with upregulation of the costimulatory molecules, 
indicating that all 4 transgenes could be inserted into the vector and result in effective infection 
and gene expression (Table 4). 
Table 4 
In vitro Infection of Human DCs with MVA-BN-Brachyury 
 
NCI Internal Data, Heery et al. (2017) 
MOI - multiplicity of infection 
Brachyury expression was present when DCs were infected with MVA-BN-Brachyury,but was 
undetectable in uninfected or MVA-WT-infected DCs (Figure 2). Similarly, expression of 
Brachyury in DCs infected with MVA-BN-Brachyury [Multiplicity of Infection (MOI) = 10] was 
evaluated by immunofluorescence using a monoclonal anti-Brachyury antibody (Abcam). These 
results indicate that the MVA-BN-Brachyury vector is able to infect human DCs, resulting in 
upregulation of Brachyury as well as 3 costimulatory molecules (TRICOM). 

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Figure 2 
Detection of Brachyury Expression by Western Blot Analysis 
 
Expression of Brachyury was evaluated by Western blot analysis with a monoclonal rabbit anti-Brachyury antibody 
(Ab) (clone 54-1). Glyceraldehyde 3-phosphate dehydrogenase expression is also shown. (MW = molecular weight 
marker). (Figure adapted from Heery et al. (2017)) 
Figure 3 
Detection of Brachyury by Immunofluorescence 
 
Heery et al. (2017) 
Expression of Brachyury was evaluated by immunofluorescence with a monoclonal anti-Brachyury Ab (Abcam). 
(Green indicates Brachyury expression, gray indicates DAPI-stained nuclei.) 
  
 

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2.4.5 Induction of Human T Cells by MVA-BN-Brachyury 
In order to investigate the ability of MVA-BN-Brachyury to expand Brachyury-specific T cells 
from the blood of normal donors, DCs were prepared from PBMCs and infected with MVA-WT, 
MVA-TRICOM, or MVA-BN-Brachyury vectors. Brachyury-specific T cells were stimulated 
with irradiated DCs. Supernatants were collected and evaluated for type I interferon 
(IFH)-gamma production by Enzyme-linked Immunosorbent Assay (ELISA). Shown is the IFN-
gamma production in response to MVA-BN-Brachyury vs. MVA-WT-infected DCs (Figure 4).  
 
Figure 4 
Brachyury-specific CD8+ T cell Stimulation by MVA-BN-Brachyury-infected 
DCs Compared with MVA-TRICOM-infected DCs 
 
Heery et al. (2017) 
CD4+ T cells from normal-donor PBMCs were exposed to either MVA-WT or MVA-BN-
Brachyury-infected DCs and then exposed to a control human serum albumin (HSA) or 
Brachyury protein. The CD4+ T cells exposed to MVA-WT did not proliferate in response to 
HSA or Brachyury, but the CD4+ T cells exposed to MVA-BN-Brachyury DCs proliferated 
significantly better when exposed to Brachyury protein compared with HSA (Figure 5). These 
results indicate MVA-BN-Brachyury is able to effectively expand CD4+ Brachyury-specific 
T cells from the blood of normal donors, as compared to the MVA-WT vector.  
 

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Figure 5 
MVA-BN-Brachyury (and not MVA-WT)-infected Human DCs Expand CD4+ T 
cells from PBMCs of Normal Donors that Recognize Purified Brachyury Protein 
 
Heery et al. (2017) 
2.5 MVA-BN-Brachyury and FPV-Brachyury Vaccines 
2.5.1 Characteristics of MVA-Bavarian Nordic (MVA-BN) Vector and FPV Vector 
Backbones 
MVA-BN effectively infects mammalian cells. Infection of mammalian cells results in 
transcription of the viral genes, but no MVA-BN is released from the cells due to a genetic block 
in the viral assembly and egress. The infected cells eventually undergo apoptosis (programmed 
cell death). MVA-BN replicates efficiently in chick embryo fibroblasts cells and probably also in 
certain other avian cell lines. Despite its high attenuation and reduced virulence, in preclinical 
studies MVA-BN has been shown to elicit both humoral and cellular immune responses to 
vaccinia and genes cloned into the MVA genome. MVA-BN is a potent inducer of type I 
interferon (IFN) in human cells. Like other MVA, MVA-BN expresses a soluble interleukin-1 
receptor, which has been implicated as an antivirulence factor for certain poxviruses (Alcami and 
Smith, 1992). MVA does not express soluble receptors for IFN-, IFN-/, tumor necrosis factor, 
or CC chemokines (Antoine et al., 1998). 
MVA-BN is a further attenuated MVA strain that has lost its ability to replicate in most 
mammalian cell types, including almost all human cell lines, and is safe in severely 
immunocompromised animals (AGR129 mice). The hallmark of MVA-BN is the fact that it does 
not productively replicate in the human keratinocyte cell line HaCat, the human cervix 
adenocarcinoma cell line HeLa, the human embryo kidney cell line 293 (HEK293), and the 

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human bone osteosarcoma cell line 143B. However, like other MVA strains, MVA-BN 
effectively infects mammalian cells. 
Fowlpox virus is a member of the genus Avipox, which is evolutionarily divergent from vaccinia 
virus and serologically non-cross-reactive (Beukema et al., 2006, Taylor et al., 1988). Immune 
responses to vaccinia do not block infection and immunization with fowlpox-based vectors. 
Hence vaccinia-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, Webster et al., 2006, Essajee and Kaufman, 2004). 
The recombinant FPV-Brachyury 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 demonstrating the successful heterologous 
prime-boost concept using recombinant vaccinia and fowlpox virus based vaccines.  
2.5.2 Description of MVA-BN-Brachyury and FPV-Brachyury 
BN-Brachyury is comprised of two recombinant poxviral vectors to be used together in a prime-
boost vaccination regimen. The priming vector is a highly attenuated, non-replicating vaccinia 
virus Modified Vaccinia Ankara-Bavarian Nordic-Brachyury (MVA-BN-Brachyury) and the 
boost is a recombinant fowlpox virus (FPV-Brachyury).  
BN-Brachyury has been designed to consist of four human transgenes to elicit a specific and 
robust immune response to a variety of cancers. Both viral vectors for BN-Brachyury co-express 
the Brachyury human TAA and three human costimulatory molecules: B7.1 (also known as 
CD80), intercellular adhesion molecule-1 (ICAM-1, also known as CD54), and leukocyte 
function-associated antigen-3 (LFA-3, also known as CD58). The three costimulatory molecules 
(or TRIad of COstimulatory Molecules, TRICOM™) are included to maximize the immune 
response to the Brachyury human TAA.   

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The anti-tumor mechanism of action for BN-Brachyury poxvirus-based immunotherapy is to 
induce the generation of tumor antigen-specific killer T cells capable of infiltrating the tumor. 
This tumor-specific T cell immune response is aimed to target and kill antigen-expressing tumor 
cells throughout the patient’s body. 
2.5.3 Previous Clinical Experience 
A Phase 1 dose escalation clinical trial (3+3) of MVA-BN-Brachyury was recently completed 
and enrolled 25 patients with advanced cancer and 13 with chordoma (NCT 02179515). Dose 
escalation was performed with 3 dose levels [Dose Level (DL)1=nominal 2 x 108, DL2=nominal 
4 x 108 and DL3=nominal 8 x 108 Infectious units] with vaccine administered in 3 cycles every 4 
weeks. In total, 3 patients enrolled on DL1, 17 on DL2, and 18 on DL3. MVA-BN-Brachyury 
vaccine was well tolerated with no dose limiting toxicities. The maximal tolerated dose was not 
reached. Two other serious AEs occurred, a hip fracture after a fall and a colonic obstruction due 
to disease progression. No serious adverse event was related to vaccine. AEs occurring in >2 
unique patients included diarrhea (7.9%), fever (18%), flu-like symptoms (34%), and injection 
site reaction (74%). One grade 3 adverse event, diarrhea, was related to vaccine, and resolved 
without intervention after 48 hours. All other adverse events related to vaccine were grade 1 or 2 
with short duration. Two deaths occurred on trial, both due to complications of rapid disease 
progression, unrelated to vaccine. Immune responses were analyzed in 29 patients. Brachyury-
specific T cell responses were observed at each dose level: 66% (2/3) of patients at DL1, 80% 
(12/15) at DL2, and 90% at DL3. At DL2 and DL3, ~80% of the patients that developed 
Brachyury-specific-T cells demonstrated responses in both CD4 and CD8 T-lymphocytes (Heery 
et al., 2017). 
A Phase 1 evaluation of MVA-BN-Brachyury followed by FPV-Brachyury is currently ongoing. 
This trial will enroll up to 10 patients. Two prime doses of MVA-BN-Brachyury will be given 
subcutaneously for one dose each on Week 0 and Week 4. Boost with FPV-Brachyury will be 
given subcutaneously monthly for 6 doses then given every 12 weeks for 6 doses. The primary 
objective of the trial is to determine the safety and tolerability of the recommended Phase 2 dose 
of MVA-BN-Brachyury vaccine followed by FPV-Brachyury (NCT03349983). 
Recombinant vaccinia and fowlpox vectors are most effective when used in combination in 
prime-boost regimens. By priming with recombinant vaccinia virus and then boosting repeatedly 
with the corresponding recombinant fowlpox virus, maximum immune responses to the 
expressed tumor antigens can be obtained. This phenomenon has been demonstrated in animal 
models (Dale et al., 2006) and has been supported by the results from the completed Phase 1 and 
Phase 2 PROSTVAC TRICOM trials conducted by the National Cancer Institute (Kantoff et al., 
2010). Clinical evaluation of the Phase 1 clinical trial of MVA-BN-Brachyury vaccine 
(NCT02179515) was limited due to the lack of long-term booster dosing. The additional of 
fowlpox booster doses should allow future trials in Phase 2 to fully evaluate the clinical potential 
of MVA-BN/FPV-Brachyury. An extensive clinical dataset concerning the use of the fowlpox 
virus vector at a dose of 1 x 109 (pfu)/0.5 mL has been developed, consisting of approximately 

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300 Patients included in 7 PANVAC clinical trials. In addition, over 100 patients have also been 
included in more than 12 National Cancer Institute (NCI)-sponsored PROSTVAC clinical trials, 
followed by more than 800 patients already participating in an ongoing Phase 3 trial investigating 
PROSTVAC-V/F. As a result, this fowlpox dose level has demonstrated to be well tolerated. 
Therefore, the FPV-Brachyury dose planned to be used in the present trial equals the ones 
employed during the clinical development programs of PANVAC and PROSTVAC. 
To date, clinical data (safety and immunogenicity) with MVA-BN smallpox vaccine and MVA-
BN based recombinant vaccines, at doses up to at least 5 x 108 TCID50 (nominal titer), have been 
generated in more than 10,500 human patients including children (aged 6 months to 6 years) and 
at-risk populations such as patients infected with HIV or suffering from cancer. In contrast to the 
experience with conventional, replicating smallpox vaccines, no safety signals have been detected 
and no cardiac risk was identified during clinical development of MVA-BN and its recombinants. 
2.5.4 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 even 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 and cancer patients 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 Investigator’s Brochure.  
Adverse Drug Reactions  
Table 5 summarizes the pooled Adverse Drug Reaction (ADR) data of all completed MVA-BN 
trials. 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 displayed in Table 5 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. 
Table 5 
Summary of Suspected ADRs Reported by ≥ 1% in Vaccinia-Naïve vs. Vaccinia-
Experienced Populations in Completed MVA-BN Clinical Trials* 
  
Preferred Term 
Naive (N = 7135) 
 Experienced (N = 728) 
n 
Frequency (%) 
n 
Frequency (%) 
Injection site pain 
5844 
81.9% 
541 
74.3% 
Injection site erythema 
4547 
63.7% 
502 
69.0% 
Injection site swelling 
3390 
47.5% 
414 
56.9% 
Injection site induration 
2954 
41.4% 
361 
49.6% 
Injection site pruritus 
2738 
38.4% 
197 
27.1% 
Fatigue 
2228 
31.2% 
197 
27.1% 
Rigors/chills 
665 
9.3% 
19 
2.6% 

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Preferred Term 
Naive (N = 7135) 
 Experienced (N = 728) 
n 
Frequency (%) 
n 
Frequency (%) 
Injection site nodule 
185 
2.6% 
10 
1.4% 
Injection site 
discolouration 
191 
2.7% 
0 
0.0% 
Injection site haematoma 
91 
1.3% 
16 
2.2% 
Axillary pain 
90 
1.3% 
1 
0.1% 
Injection site warmth 
67 
0.9% 
18 
2.5% 
Headache 
2127 
29.8% 
147 
20.2% 
Dizziness 
43 
0.6% 
9 
1.2% 
Myalgia 
2367 
33.2% 
157 
21.6% 
Arthralgia 
199 
2.8% 
7 
1.0% 
Pain in extremity 
146 
2.0% 
1 
0.1% 
Nausea 
1036 
14.5% 
66 
9.1% 
Body temperature 
increased 
254 
3.6% 
15 
2.1% 
Pyrexia 
96 
1.3% 
3 
0.4% 
Appetite disorder 
218 
3.1% 
0 
0.0% 
Pharyngolaryngeal pain 
23 
0.3% 
8 
1.1% 
Source: Table 11, MVA-BN IB, Ed. 21 
* POX-MVA-001, -002, -004, -005, -006, -007, -008, -009, -010, -011, -013, -023, -024, -027, -028, -029, -030, 
036, -037, -03X, HIV-NEF-004 and HIV-POL-002; 7 subjects in POX-MVA-009 received Dryvax either on 
the same day or within 7 days after MVA-BN administration and were therefore not included to avoid a 
potential bias in adverse event reporting.   
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.  
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. After 
vaccinating more than 7,800 subjects with MVA-BN in completed clinical trials, no case of 
myocarditis, confirmed pericarditis, endocarditis or any other type of cardiac inflammatory 
disease (or related syndromes) was reported. Therefore MVA-BN is considered not to cause any 
inflammatory cardiac events as observed with the use of replicating smallpox vaccines like 
Dryvax and ACAM2000. 
 

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Serious Suspected Adverse Drug Reactions  
As of 31 July 2017, a total of 7 (7 out of 7,871 vaccinated subjects = 0.09%) serious suspected 
ADRs have been reported for MVA-BN smallpox vaccine in completed and ongoing trials (Table 
6).  
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 
could be detected. 
 
 

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Table 6 
Serious Suspected Adverse Drug Reactions (Assessed by the Investigator to be at 
Least Possibly Related to MVA-BN) 
Trial 
Code 
Age/ 
Gender 
Days After 
Vaccinatio
n 
Event 
Outcome 
Underlying Diseases/ 
Circumstances 
PI  
Assess-
ment  
BN Opinion 
POX-
MVA-
005 
30/ 
Male 
70 days 
after second 
vaccination 
Sarcoidosis 
Stable 
and 
asympto-
matic 
Urinary tract infection with 
Chlamydia trachomatis at 
time of first symptoms 
(arthralgia) 
Possibly 
related 
Possibly 
related 
POX-
MVA-
005 
31/ 
Female 
26 months 
after second 
vaccination 
Crohn’s 
disease 
Stable 
and 
asympto-
matic 
under 
therapy  
Abnormal lab results 
(elevated alkaline 
phosphatase, absolute 
neutrophils and platelet 
counts) at screening for 2-
year follow-up trial POX-
MVA-023 (excluded) 
Possibly 
related 
Possibly 
related  
POX-
MVA-
008 
28/ 
Female 
8 days after 
second 
vaccination 
Transitory 
ocular 
muscle 
paresis 
Resolved 
without 
sequelae 
No relevant medical history 
Probably 
related 
Possibly 
related 
POX-
MVA-
010 
30/ 
Female 
133 days 
after second 
vaccination 
Congestive 
heart failure 
due to 
cardio-
myopathy 
Stable 
under 
cardiac 
medi-
cations 
Surgery for ventricular 
septal defect as child. HIV 
infection. Concomitant 
(denied, therefore previously 
unknown to BN) 
participation in a Growth-
Hormone Releasing 
Hormone (GH-RH) trial; 
event also assessed as 
possibly related to GH-RH 
Possibly 
related 
Unlikely 
related 
POX-
MVA-
011 
39/ 
Female 
1 day after 
second 
vaccination 
Simple 
pneumonia 
and pleurisy 
Resolved 
without 
sequelae 
HIV infection (CD4 count 4 
weeks prior to second 
vaccination was 
299 cells/µL). History of 
chronic obstructive 
pulmonary disease. Acute 
sinusitis and nasal 
congestion due to 
swimmer’s ear which 
triggered hospital 
admittance. 
Possibly 
related 
Unlikely 
related 
POX-
MVA-
036 
27/ 
Female 
0 days after 
second 
vaccination 
Throat 
tightness and 
other 
hypersensitiv
ity symptoms 
such as 
hives, 
pruritus, 
tender 
vaccination 
site, swollen 
axilla, 
angioedema 
of forearms 
Resolved 
without 
sequelae 
The subject received her 
second dose of MVA-BN 21 
days after the first dose and 
after 2 hours developed 
symptoms such as skin 
reactions and throat tightness 
which was responsive to 
epinephrine treatment. She 
had no wheezing and was 
not hypotensive. Symptoms 
subsided after several days 
under prednisone and 
diphenhydramine treatment. 
She has a family history of 
Possibly 
related 
Possibly 
related 

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allergies and a medical 
history of shingles. She has 
received multiple vaccines 
before but never had 
previous hives or other 
problems with vaccines. 
POX-
MVA-
036 
30/ 
Male 
117 days 
after first 
vaccination 
Non ST 
segment 
elevation 
myocardial 
infarction 
Resolved 
without 
sequelae 
Positive family history for 
cardiovascular diseases (both 
grandfathers had myocardial 
infarctions in their 50ies, 
father had blood clots), as 
well as overweight with a 
BMI above 33. A few days 
before event onset, subject 
returned from a trip to India 
with diarrhea and was started 
on ciprofloxacin treatment 
(which per US prescribing 
information is associated 
with angina pectoris and 
myocardial infarction). He 
showed chest pain and 
increased troponin I, but no 
ST segment changes in the 
ECG and no coronary artery 
disease in cardiac 
catheterization. A post-
infectious myocarditis 
(published case reports exist 
for campylobacter, shigella, 
and salmonella) was 
considered as alternative 
etiology for the reported 
event. 
Possibly 
related 
Unlikely 
related 
Source: Table 22, MVA-BN IB, Ed. 21 
2.5.5 Immunogenicity Overview of MVA-BN  
MVA-BN was tested for safety and immunogenicity among healthy volunteers in 3 Phase 1 and 2 
dose finding trials (Frey et al., 2007, von Krempelhuber et al., 2010, Vollmar et al., 2006). Across 
these trials, a linear dose relationship was observed between the vaccine doses and both vaccinia 
ELISA and Plaque Reduction Neutralization Test (PRNT) titers. Maximum ELISA 
seroconversion rates and peak titers were reached 2 weeks after the second vaccination, with 
100% seroconversion after the second dose for all dose groups receiving at least 2 x 107 TCID50 
per 0.5 mL dose of MVA-BN. Statistical analysis indicated lower doses to be inferior to the 
standard dose tested throughout all dose ranging trials, whereas the standard dose achieved 
ELISA seroconversion rates between 81% and 100% already after the first dose. For the PRNT, 
the same trend was observed with about 77% seroconversion rates 2 weeks after the second 
MVA-BN administration in all groups receiving the highest dose. 

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The early onset of seroconversion and the higher titers of total and neutralizing antibodies 
combined with an excellent safety profile qualified the dose of at least 5 x 107 TCID50 as the most 
suitable human dose. The final optimal (standard) dose and schedule for the general population 
was decided to be 2 doses of at least 5 x 107 TCID50 MVA-BN administered SC 4 weeks apart. 
2.5.6 Safety Overview of Vaccinia and Fowlpox-based Vaccines (PROSTVAC) in 
Completed and Ongoing Clinical Trials 
The supportive clinical data described below were generated in the clinical development program 
of PROSTVAC (another poxvirus-based cancer immunotherapy in development by BN, 
consisting of a vaccinia-based prime regimen followed by a fowlpox-based boost regimen) in 
oncologic indications. The sections below describe the overall experience and safety profile of 
PROSTVAC, including the complete regimen, using the same fowlpox vector as for FPV-
Brachyury. Clinical data investigating the fowlpox-based PROSTVAC boost component in an 
isolated fashion are not available. PROSTVAC alone and in combination with low dose GM-CSF 
appears to be well-tolerated. This is supported by data from completed and ongoing trials of 
PROSTVAC without concomitant chemotherapy or radiation. The most frequently reported AEs 
were injection site reactions.  
In a Phase 2 clinical trial (TBC-PRO-002), > 10% of patients reported the following events: 
injection site reactions (injection site erythema, injection site induration, injection site pain, 
injection site pruritus, injection site swelling), chills, fatigue, pyrexia, peripheral edema, nausea, 
diarrhea, constipation, arthralgia and dizziness. Similar events were observed in other non-
randomized, open-label trials and a completed Phase 3 trial. No dose-limiting toxicities have been 
reported. In the Phase 2 trial, a total of 16 treatment-emergent Serious Adverse Events (SAEs) 
occurred in seven patients (five patients in the PROSTVAC group (6.1%) and two in the control 
group (5%)). Two of the SAEs in the PROSTVAC treated group were deemed by the investigator 
to be possibly treatment related, myocardial infarction and thrombotic thrombocytopenic purpura 
(both occurred in one patient), and one event in the control group (pyrexia). In other open label 
trials, possibly related SAEs of fever, chills and bone pain and urticarial, myalgia, pain and joint 
effusion have been reported with PROSTVAC. Across all trials, laboratory evaluations revealed 
no untoward effects of treatment. No vaccinia-related or autoimmune events were noted. 
In completed clinical trials in which PROSTVAC has been used in combination with other 
products, reported AEs have not been clinically significantly different from those reported for the 
combinatory agent (docetaxel, flutamide, ipilimumab, or Sm-EDTMP) alone. In these trials, 
toxicities related to the combinatory agent were reported more commonly than those related to 
PROSTVAC and GM-CSF. 
In the PROSTVAC Phase 3 trial BNIT-PRV-301, the AEs reported in the trial were similar to 
previous PROSTVAC monotherapy trials. AEs which occurred in at least 10% of patients include 
general disorders and administration site conditions (injection site erythema, injection site pain, 
fatigue, injection site pruritus, injection site swelling, fever, injection site induration, influenza 

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like illness, asthenia, chills), gastrointestinal disorders (nausea),musculoskeletal disorders 
(arthralgia, back pain, Myalgia), and Nervous system disorders (headache). Ten patients reported 
13 SAEs that were submitted to regulatory authorities as Suspected Unexpected Serious Adverse 
Reactions in an expedited manner. 
The following AEs have been categorized as having a reasonable possibility of being related to 
PROSTVAC. Those marked with * have been reported at least once as Grade 3 (severe). The 
ADRs listed are therefore considered as reference safety information for FPV-Brachyury. 
Table 7 
ADRs for FPV (Originating from PROSTVAC Program) 
 
General disorders and administration site 
conditions:  
 
ISRs, injection site erythema, injection site 
induration*, injection site pain, injection site 
pruritus, injection site swelling, pyrexia *, chills, 
peripheral edema, fatigue, influenza-like illness 
 
 
Gastrointestinal disorders: 
 
Nausea* 
 
 
Nervous system disorders: 
 
Dizziness 
 
 
Musculoskeletal and connective tissue disorders:  
 
Myalgia* 
 
Source: Table 9, BN-Brachyury IB, Ed. 3.0 
2.5.7 Rationale for BN-Brachyury Prime-Boost Regimen 
Recombinant vaccinia and fowlpox vectors are most effective when used in combination in 
prime-boost regimens. By priming with recombinant vaccinia virus and then boosting repeatedly 
with the corresponding recombinant fowlpox virus, maximum immune responses to the 
expressed tumor antigens can be obtained. This phenomenon has been demonstrated in animal 
models (Dale et al., 2006) and has been supported by the results from the completed Phase 1 and 
Phase 2 PROSTVAC TRICOM trials conducted by the National Cancer Institute (Hodge et al., 
2009, Arlen et al., 2007). Results for a Phase 1 clinical trial of MVA-BN-Brachyury vaccine 
(NCT02179515) were described in Section 2.5.3. Clinical evaluation was limited due to the lack 
of long-term booster dosing. The additional of fowlpox booster doses should allow future trials in 
Phase 2 to fully evaluate the clinical potential of MVA-BN/FPV-Brachyury. 

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2.5.8 Rationale for Treatment Regimen of BN-Brachyury Plus Radiation 
The basic concept of this clinical trial is to evaluate the therapeutic effect of triggering a 
Brachyury-specific immune response in patients bearing a tumor with high level expression of 
the target antigen, Brachyury. Chordoma, because it is a tumor defined by the expression of 
Brachyury, is an ideal candidate to evaluate the efficacy of this therapeutic cancer vaccine. 
However, previous clinical experience [GI-6301(Heery et al., 2015) and MVA-Brachyury (Heery 
et al., 2015)] with chordoma and in vitro work has demonstrated that a strong Brachyury-specific 
immune response is not adequate to get T cell mediated killing of tumor cells (Figure 6).  
Figure 6 
Lysis of UCH-1 Cells by Brachyury-specific T Cells 
 
UCH-1 cells were left untreated or treated for 48 hours 
in the presence of 100 ng/ml of recombinant human 
IFN-gamma and the co-cultured with Brachyury-
specific T cells. Minimal killing was observed in the 
absence of IFN-gamma, and a statistically significant 
improvement was observed after exposure to IFN-
gamma. 
 
NCI Internal Data 
 
JHC-7 chordoma cells were labeled with 111In and used 
as targets in an overnight CTL lysis assay with 
Brachyury-specific T cells as effectors, at a ratio 
target:effectors equal to 1:20. Minimal killing was 
observed with exposure to brachyury-specific T cells 
alone, but after exposure to 8Gy of radiation in a single 
fraction, there was a significant increase in T cell 
mediated killing. 
NCI Internal Data, Gameiro et al. (2016)  
In fact, only 2 patients in a previous clinical trial responded to vaccine treatment, and both of 
those patients had previous radiotherapy in a recent time period (GI6301) (Heery et al., 2015). In 
a previous trial of MVA-Brachyury-TRICOM, in which strong Brachyury-specific immune 
responses (Heery et al., 2017) were observed, no evidence of objective antitumor effect was 
observed. This finding was consistent with the previous observation that chordoma is 
immunologically difficult to target due to defects in the antigen processing machinery (Campoli 
and Ferrone, 2011, Ferrone, 2013). This finding was also consistent with the preclinical 
observation that sublethal doses of radiation could result in improved antigen processing 
machinery function, induce immunogenic modulation, and improve T cell mediated killing in a 

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variety of tumor types (Garnett et al., 2004). Based on these findings, in vitro work was 
performed to determine if T cell mediated killing of chordoma cells could be improved after 
radiotherapy. Indeed, treating chordoma cell lines with 8Gy of radiation, an amount sublethal to 
the tumor cells, resulted in improvement of T cell mediated killing from <5% (non-irradiated) to 
>60% (irradiated) (Bernstein et al., 2015, Gameiro et al., 2016). This finding supports the clinical 
observation from the use of another Brachyury vaccine and provides the rationale for the design 
of the treatment regimen in this clinical trial. 
2.5.9 Trial Population 
The population proposed for inclusion in this trial are male and female patients at least 12 years 
old with advanced chordoma who are planning to be treated with radiotherapy to at least one 
lesion. Inclusion of adolescents (12 – 17 years) is recommended in appropriate oncology trials 
(Chuk et al., 2017). As noted in Section 2.2, the disease course in adolescents appears to more 
closely approximate the disease course of chordoma in adults. In an effort to demonstrate clinical 
activity in the population most likely to be eligible for this treatment, adolescents have been 
included. 
2.5.10 Dose Justification 
To date, MVA-BN based vaccines have been delivered to adults and children ages 6 months to 
6 years. A single trial was conducted in children evaluating the safety, dose response and 
immunogenicity of a recombinant MVA-BN measles vaccine in children aged 6 months to 
6 years. Sixty children received a single 0.5 mL SC injection on days 0 and 28 of either 1 x 107 
TCID50 or 1 x 108 TCID50. There were two SAEs reported, none of which were vaccine related. 
The vaccine was well tolerated at the MVA-BN dosage of 1 x 108 Inf.U in children aged 
6 months to 6 years, which is the same dosage as the MVA-BN smallpox vaccine specified in the 
CDC held preEUA (Emergency Use Authorization) for children > 1 year and adults.   
An extensive clinical dataset concerning the use of the fowlpox virus vector at a nominal dose of 
1 x 109 Inf.U/0.5 mL has also been developed in the adult population, consisting of 
approximately 300 patients included in 7 PANVAC clinical trial and more than 900 patients in 
PROSTVAC clinical trials. As a result, this fowlpox dose level was demonstrated to be well 
tolerated with no significant safety findings.  
For other vaccines administered by SC injection, the dosage amount and volume for adults and 
children is the same. For example, the prescription information for measles, mumps and rubella 
(MMR® II) specifies a dose of 0.5 mL in individuals 12 months of age or older. The prescription 
information for varicella (VARIVAX) allows for two 0.5 mL doses for children 12 months to 12 
years of age, with a minimum interval of 3 months between doses and specifies two 0.5 mL doses 
for children ≥ 13 years and adults, with a minimum interval of 4 weeks between doses.  

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Therefore, based on the similarity of vaccine dosing among adolescents and adults, and an 
acceptable safety profile of the MVA-BN measles vaccine in children between 6 months and 
6 years when given at the same dosage of the MVA-BN smallpox vaccine, the recommended 
MVA-BN-Brachyury dosage regime for adolescents and adults is the same. The target dose of 
MVA-BN-Brachyury is based on the Phase 1 clinical trial of 5 x 108 Inf.U per injection and the 
target dose of FPV-Brachyury is based on previous trials of other recombinant FPV vaccines 
using 1 x 109 Inf.U. 
The selection of the minimum allowable dose of radiation is based on the preclinical in vitro 
work where 8Gy of radiation was applied to the chordoma cells (Gameiro et al., 2016). It is likely 
that, in most cases, a higher dose of radiotherapy may be used clinically, but a minimum 
threshold of biologic effect is set based on the preclinical work. In this clinical trial, the dose of 
radiation will be determined, in each case, by the treating radiation oncologist as per standard 
treatment guidelines. 
3 Trial Objectives 
Primary Objectives:  
To determine if the combination of BN-Brachyury administered with radiotherapy will result in a 
clinically meaningful ORR when compared with historical control. 
Secondary Objectives: 
• 
To confirm the safety profile of BN-Brachyury plus radiation therapy 
• 
Progression Free Survival (PFS) by modified RECIST 1.1 criterion 
• 
Improvement in clinical symptoms as measured by the BPI-SF pain assessment 
Exploratory Objectives: 
• 
Evaluate the differences in clinical outcome measures by location of primary tumor (Sacral 
vs. Mobile Spine vs. Clival) 
• 
Measure adverse event profile by location of primary tumor 
• 
To evaluate other clinical endpoints that might be indicative of clinical benefit: 
o ORR by standard RECIST 1.1 
o PFS by other criteria ((Choi, 2007) and volumetric (Fenerty et al., 2016), by standard 
RECIST 1.1) 
• 
To evaluate changes in immune and tumor related biomarkers of pre- versus post-baseline 
samples  
o Peripheral blood mononuclear cells (PBMC) 

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▪ Brachyury and other Tumor associated antigen (TAA) specific T cell 
activation  
▪ Immune cell subset quantification and characterization  
 
o Serum  
▪ Analysis for soluble factors associated to immune response e.g. antibodies 
or cytokines 
4 Trial Design 
4.1 Experimental Design 
This is a single arm Phase 2 clinical trial using a Simon 2-stage optimal design. The goal is to 
demonstrate that BN-Brachyury plus radiation therapy can induce objective radiographic 
responses in patients. In stage 1, a minimum threshold of activity will be needed to proceed to 
stage 2. Note, for this protocol enrollment indicates the patient receives at least their first 
treatment. 
Stage 1: Enroll 10 patients. If objective response is not achieved in any patients, the trial will be 
stopped for lack of activity. If objective response is achieved in ≥1 patients, the trial will proceed 
to stage 2. If any patient is not evaluable for the primary endpoint, the patient may be replaced. 
Stage 2: Enroll an additional 19 patients for total of 29 patients. If any patient is not evaluable for 
the primary endpoint, replacement patients may be enrolled until a total of 29 patients are 
evaluable for the primary endpoint. 
4.2 Description of Trial Procedure 
Patients will be treated with 2 priming doses of MVA-BN-Brachyury (Doses 1 and 2) and 1 dose 
of FPV-Brachyury (Dose 3) prior to initiation of radiotherapy. MVA-BN-Brachyury will be 
administered on Day 0 and approximately Day 14 (+ / - 2 days) followed by FPV-Brachyury on 
approximately Day 28 (+ / - 2 days). Radiotherapy will begin at least 2 weeks and not more than 
4 weeks after first administration of FPV-Brachyury (Dose 3). Radiotherapy will proceed 
according to the dose and schedule selected by the treating radiation oncologist with guidelines 
detailed in Section 6.3.1.2. The trial team must collect documentation of the dose and schedule of 
radiotherapy administered. The dose and schedule must comply with radiotherapy minimum 
requirements as defined in Section 6.3.1. 
At least 2 weeks following completion of radiotherapy (or upon resolution of any reversible AEs 
related to radiotherapy to Grade 1 or baseline if ongoing beyond 2 weeks), the patient will resume 
vaccination with FPV-Brachyury (Dose 4) and proceed to ongoing booster doses with FPV-
Brachyury at 4-week intervals until 4 booster doses with FPV-Brachyury have been administered 
(Doses 4, 5, 6, 7). Subsequent vaccine doses will be administered in 12-week intervals through 

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approximately 2 years beyond completion of radiotherapy (Doses 8, 9, 10, 11, 12, 13). A final 
visit will occur 30 days after the last treatment visit.   
 
Figure 7 
Trial Vaccine Schedule 
 
4.2.1 Screening Phase 
The screening evaluation will be conducted within 16 days before initiating treatment unless 
otherwise specified: 
4.2.1.1 Clinical Evaluation  
• 
History and physical examination including vital signs (blood pressure, pulse, oxygen 
saturation, and temperature) Special attention should be paid to any history of vaccine 
allergies.  
• 
Height and weight 
• 
ECOG Performance status determination 
4.2.1.2 Laboratory Studies 
To be performed at any time before Screening/ Baseline: 
• 
Confirmation of diagnosis by Site Pathology Department. 

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To be performed within 6 months prior to Screening/ Baseline: 
• 
Screening for HIV 
• 
Screening for Hepatitis B and C. 
To be performed within 16 days prior to Screening/ Baseline: 
• 
Complete blood count plus differential and platelet count 
• 
Serum chemistries (Na+, K+, Cl-, CO2, glucose, BUN, creatinine, albumin, calcium, 
alkaline phosphatase, ALT, AST, total bilirubin, TSH)  
• 
Antinuclear antibody titer (ANA) 
• 
Beta-HCG for females of childbearing potential (repeated Beta-HCG [serum or urine] tests 
within 48 hours prior to treatment).  Females of childbearing potential: A female of 
childbearing potential is a woman who: 
o Has started menses  
o Has not undergone a hysterectomy or bilateral oophorectomy 
o Has not been naturally postmenopausal for at least 24 consecutive months (i.e. has had 
menses at any time in the preceding 24 consecutive months) 
o Women of childbearing potential and sexually active males must be strongly advised to 
use an accepted and effective method of contraception or to abstain from sexual 
intercourse for the duration of their participation in the trial 
• 
CD4:CD8 ratio, CD3, 4, 8, 19 subsets and Natural Killer (NK) markers (baseline, about day 
28 and around day 85 prior to vaccination) 
4.2.1.3 Electrocardiogram (ECG) 
Within 28 days prior to protocol enrollment. 
4.2.1.4 Scans and X-Rays 
To be performed within 28 days prior to the protocol enrollment: 
• 
Computed Tomography (CT) of the chest/abdomen/pelvis 
• 
Magnetic resonance imaging (MRI) of target lesions if present in: sacrum, spine, or clivus 
o MRI should include a T2 weighted fat-suppressed technique and/or fluid-attenuated 
inversion recovery or short TI Inversion Recovery to ensure differentiation from 
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4.2.2 Active Trial Phase 
Medical assessment and ECOG performance status will be completed within 3 days prior to each 
vaccination. Medical assessments will include a complete neurologic examination including 
documentation of cranial nerve, motor, sensory, cerebellar, and deep tendon reflex examinations. 
4.2.2.1 Laboratory Assessments 
• 
Complete Blood Count (CBC)/differential, with platelet count. 
• 
Serum chemistries (Na+, K+, Cl-, CO2, glucose, BUN, creatinine, albumin, calcium, 
alkaline phosphatase, ALT, AST, total bilirubin) 
• 
Antinuclear antibody titer (if autoimmune toxicity is observed) 
• 
CD4:CD8 ratio, CD3, 4, 8, 19 subsets and NK markers (to be drawn only on same day as 
blood for correlative biomarker studies research labs; see Section 7) 
These laboratory tests will be drawn prior to each vaccination for all patients unless otherwise 
indicated. For FOCBP, a serum or urine Beta-HCG test will be drawn within 48 hours prior to 
each vaccination. At a minimum, CBC, serum creatinine, and electrolytes will be obtained prior 
to each vaccination. Laboratory studies will be repeated more frequently if clinically indicated, 
and any abnormalities potentially related to treatment will be followed until they have resolved, 
or have been determined to not be treatment-related. 
4.2.2.2 Evaluation of Response 
Appropriate imaging with CT of the chest/abdomen/pelvis and MRI (if target lesion is best 
visualized by MRI) to reassess tumor extent and to determine tumor measurements will be 
performed 14 weeks after completion of radiotherapy and with each subsequent dose of vaccine 
thereafter (with windows for treatment as designated in the schedule of events, Section 1.5).   
4.2.3 After Treatment Completion 
Post-treatment follow-up will be conducted 30 (+/- 2) days after last dose of treatment. The visit 
should include a history and physical exam; labs with CBC/differential and serum chemistries; 
assessment of trial drug AEs; RECIST 1.1 assessment; and CT chest, abdomen, and pelvis, and 
MRI (if target lesion is best visualized by MRI). If patient had abnormal physical exam findings 
or abnormal lab values at the off-treatment time point, then the patient should have follow-up 
visit with the primary oncologist to focus on the abnormal finding(s). Results and report findings 
should be faxed or emailed to the trial team. 
Once the 30 day follow up assessment is completed, the patient is then taken off trial. 

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Patients removed from trial for any reason must be followed for at least 30 days after the last 
dose of vaccine or until all toxicities have resolved to baseline or stabilized, whichever is later. 
4.2.4 Unscheduled Visits 
Additional visits to the clinic may be necessary between scheduled visits based on a patient’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 Withdrawal from Vaccination 
Patients will be withdrawn from vaccination if any of the following is true: 
• 
Target lesion disease progression as determined by 
o Radiographic disease progression by standard RECIST 1.1 
o Symptomatic disease progression by symptoms with concurrent evidence of any tumor 
enlargement 
o NOTE: A patient may continue on trial, at the investigator’s discretion, with 
progression if he/she is eligible for local intervention for a non-target lesion 
progression 
o NOTE: A patient may remain on trial after initial evidence of target lesion disease 
progression until a confirmatory scan has been performed due to tumor swelling that 
can occur with radiotherapy and/or immunotherapy  
• 
Patient withdrawal of consent (must document patient rationale for withdrawal) 
• 
Positive pregnancy test 
• 
Intercurrent illness or medical circumstances. If at any time the constraints of this protocol 
are detrimental to the patient’s health, the patient may be removed from protocol therapy. 
In this event, the reasons for withdrawal will be documented. 
• 
Adverse events meeting the following criteria: Evidence of any ≥ Grade 3 allergic and ≥ 
Grade 3 autoimmune reaction(s) attributed to vaccine (except Grade 3 endocrine-related 
immune toxicity or Grade 3 endocrine-related immune toxicity that resolves to Grade ≤ 1 
clinically within 7 days of initiating supportive therapy); or if > Grade 2 toxicity attributed 
to vaccine persists for > 28 days, the patient will not receive further vaccine injections. 
Patients who come off treatment must be followed on trial until resolution of toxicity and 
until disease progression. 

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4.2.6 Premature Discontinuation 
Patients will discontinue the trial if any of the following are true: 
• 
Participant requests to be withdrawn from trial; in this event, the reasons for withdrawal 
will be documented. If at all possible, the patient should return for the Post Treatment 
Follow-up Visit.  
• 
A patient who is noncompliant with protocol guidelines may be removed from the trial at 
the discretion of the principal investigator. 
• 
Disease progression, as described in Removal from Protocol Therapy Section 4.2.5 
• 
Death. 
4.3 Trial Duration 
The total duration of trial for each patient is up to 29 months 
4.4 Data and Safety Monitoring Board (DSMB) 
The DSMB is a board that oversees the safety of patients participating in the trial. The primary 
responsibility of the DSMB is to review and evaluate the accumulated trial data for safety, trial 
conduct, and the integrity of the trial. 
If an event occurs which fulfills the trial halting rules (see Section 4.5 for further details) the 
DSMB will review the event in a timely manner and agree on a recommendation to halt, resume 
or terminate the trial participation of the affected patient(s) and/or the trial as a whole.  
4.5 Trial Halting Rules 
A temporary halting or termination for the trial as a whole can be decided by the DSMB 
following the occurrence of: 
• 
Unexpected (i.e. not listed in the current Investigator’s Brochure) Grade 3 or higher 
systemic reaction or lab toxicity (using National Cancer Institute [NCI] Common 
Terminology Criteria for Adverse Events [CTCAE] version 4.03 or newer) with an at least 
reasonable possibility of a causal relationship to the administration of MVA-BN-Brachyury 
vaccine (i.e., the relationship to vaccine cannot be ruled out).  
• 
Any unexpected SAE with a consequence of death 
These parameters are not all-inclusive. Other AEs could occur that would trigger a safety review. 

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If an event fulfilling the trial halting criteria reaches the investigator’s attention, the investigator 
has the liability to alert the BN Pharmacovigilance immediately (within 24 hours) and provide a 
comprehensive documentation of the event.  
5 Selection of Patients 
5.1 Recruitment Procedure 
This trial will be listed on available websites (http://www.clinicaltrials.gov, 
www.cancer.gov/clinicaltrials, http://clinicalstudies.info.nih.gov) and participants will be 
recruited from the current patient population at the site. 
5.2 Inclusion Criteria 
A subject will be eligible for inclusion in this trial 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 
MVA-BN-Brachyury 
• 
MVA-BN-Brachyury vaccine is a liquid-frozen, highly attenuated, live recombinant virus 
based on the viral vector MVA-BN. It is administered as subcutaneous application.  
• 
One MVA-BN-Brachyury vaccine vial has a nominal virus titer of at least 2.5 x 107 Inf.U 
per 0.5 mL of the drug product. The specific dose will be determined upon release testing 
of the drug product. 
• 
For further details on the MVA-BN-Brachyury vaccine, see current version of the 
Brachyury Investigator’s Brochure. 
FPV-Brachyury 
• 
FPV-Brachyury is a liquid-frozen, highly attenuated, live recombinant virus. It is 
administered as subcutaneous application. 
• 
One FPV-Brachyury vial has a nominal virus titer of 1 x 109 Inf.U in 0.5 mL of the drug 
product. The specific dose will be determined upon release testing of the drug product. 
• 
For further details on the FPV-Brachyury vaccine, see current version of the Brachyury 
Investigator’s Brochure. 

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No dose modifications will be allowed on this trial. Any patient who experiences a dose limiting 
toxicity or allergic or autoimmune toxicity as defined in Section 4.2.5 will not receive any 
additional vaccinations. 
If a scheduled dose of the vaccine is missed, the vaccine may be given within the treatment 
window specified in Section 1.5. If the patient has a delay in vaccination not due to toxicity, the 
vaccine may be delayed for up to 42 days without removal of the patient from trial. 
Dosing Delay: Patients should have resolution to ≤ Grade 1 or return to baseline of all toxicities 
prior to the start of the next injection of the vaccine. If > Grade 2 toxicity attributed to vaccine 
persists for > 28 days, the patient will not receive further vaccine injections and will be removed 
from vaccine therapy. 
6.1 Production, Packaging, and Labeling 
Both the MVA-BN-Brachyury and FPV-Brachyury 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. 
Address: 
Bavarian Nordic A/S 
The packages and vials of liquid frozen MVA-BN-Brachyury and FPV-Brachyury vaccines are 
labeled with United States Investigational New Drug Application labels. 
6.2 Shipment, Storage, and Handling 
Usage of the investigational medicinal product (IMP) is only allowed upon final approval of all 
shipment relevant paperwork by Bavarian Nordic or its authorized designee. Only patients 
enrolled in the trial may receive IMP. 
Supplies of MVA-BN-Brachyury and FPV-Brachyury will be shipped temperature controlled and 
monitored, to the clinical trial site from a central United States depot. Once at the site, the 
package should be handed over to personnel in charge of IMP preparation (e.g., the pharmacist). 
Site personnel are responsible for proper storage of IMP and upon receipt. All IMP 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-Brachyury and the FPV-Brachyury 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.  

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Additional details on the shipment, storage and handling of the MVA-BN-Brachyury and 
FPV-Brachyury can be found in a separate pharmacy manual supplied to each clinical trial site. 
6.3 Preparation, Administration, and Dosage 
Detailed trial-specific instructions on the preparation and administration of MVA-BN-Brachyury 
and FPV-Brachyury are provided in a separate pharmacy manual supplied to each clinical trial 
site.  
6.3.1 Radiotherapy 
Radiotherapy must meet minimum requirements to achieve a reasonably effective dose. The 
minimum expected dose to provide biologic rationale for the combination is 8Gy in 1 fraction for 
each target lesion. Documentation by a radiation oncologist of an equivalent or higher biologic 
dose is adequate to meet requirements for eligibility and treatment on protocol. A patient who 
does not cross this threshold is not considered to have received treatment per protocol and will 
not be assessed for response per RECIST 1.1 criteria for the primary analysis/objective. 
6.3.1.1 Minimum Radiation Treatment Requirements 
1. The minimum radiotherapy dose required for biologic effect is established based on the 
preclinical data as 8 Gy in 1 fraction. The following are examples of calculations that are 
equivalent doses biologically to 8 Gy in 1 fraction. For each patient, the treating radiologist 
should calculate the biologic equivalent dose to ensure that the minimum biologic dose is 
reached. Any dose at least meeting this equivalence is potentially eligible, given that the 
treating radiation oncologist does not believe the dose will cause harm to normal surrounding 
structures. 
a. 8 Gy in 1 fraction (8 Gy / fraction) 
b. 20 Gy in 5 fractions (4 Gy per fractions; minimally 12 Gy received) 
c. 30 Gy in 10 fractions (3 Gy/fraction; minimally 15 Gy received) 
d. 40 Gy in 20 fractions (2 Gy / fraction; minimally 20 Gy received)  
 
2. Normal tissue surrounding the tumor must be protected by the standards of the treating 
institution for that organ system. For example, if a given institution requires that no normal 
spinal cord tissue receives more than a maximum point dose of 30 Gy (using 6 Gy / fraction 
bioequivalence), the treating radiation oncologist must comply with institutional standards 
when calculating the dose to the tumor center. This capability to meet requirements 1 and 2 
must be determined for the target lesion prior to enrollment on trial. 

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6.3.1.2 Guidelines for Radiotherapy for Definitive/Unresected Chordoma Treated with 
Curative Intent: 
To allow for standardization of radiation treatments, the following recommendations are 
provided: 
For treatment of unresected primary or recurrent chordomas with gross measurable disease, the 
following treatment is recommended based on a series of experience  (DeLaney et al., 2009) 
(Park et al., 2006) (Chen et al., 2013) (Kabolizadeh et al., 2017) showing high local control with 
these treatment volumes and doses. 
Gross Target Volume (GTV):  The GTV is any gross tumor(s) visualized on the treatment 
planning CT scan and or MRI.   
CTV1 (Clinical Target Volume 1) is the GTV and tumor bed plus all tissues suspected on 
invasion by tumor on a subclinical basis. This includes 1.5 to 3 cm margin for areas of 
extraosseous extension into muscular compartments such as gluteus muscles, piriformis muscles, 
erector spinae muscles or along neurovascular bundles such as sciatic nerve; the entire involved 
vertebra; a vertebral level above and below the maximal extent of intraspinal canal involvement; 
and 0.5-1.0 cm in bone or abutting soft tissue confined by a fascial, cartilaginous, bone, or disc 
space barrier, bowel, lung interface. Generally the CTV1 dose level should be reduced to 45 to 
46.80 GyRBE (gray relative biological effectiveness) in patients with these co-morbidities: active 
autoimmune disease, insulin requiring diabetes.   
CTV1 will receive a dose of 50.4 Gy (or GyE with Relative Biological Effectiveness of 1.1 to 
1 proton: photons if given with protons) 
CTV2 will consist of the GTV plus any tumor bed with a 0.5 cm margin and should receive an 
additional dose of up to 27 Gy in 1.8 Gy per fraction or equivalent. 
Planned Target Value (PTV): The clinical target volumes will be expanded (generally by 2-5 mm 
based on institutional practices) to generate a PTV to account for the intrafraction motion 
anticipated for the target volume in the immobilized patient during the treatment delivery. The 
prescribed dose is specified to the isodose contour which encompasses the planning target 
volumes on each proton field; this must be >95%. 
6.3.1.3 Treatment Planning 
Treatment planning is to be performed using 3D CT based planning systems. For patients with 
lesions of the spine above the level of the conus, a lumbar instillation of iodinated contrast 
material is recommended for the radiation planning CT scan to fully visualize the spinal cord 
unless medically contraindicated or MRI for treatment planning/fusion can be acquired in the 
immobilized treatment position. Image fusion with the diagnostic or a dedicated treatment 
planning MRI scan should be performed to optimize target definition(s). 

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6.3.1.4 Immobilization 
The patient will be in customized head or body immobilization. The treatment planning CT is to 
be performed with the patient in this mold; contrast will be employed unless there is a history of 
contrast allergy. In these sensitive patients, there will have been obtained a diagnostic MRI with 
gadolinium to aid in the designation of tumor involved tissue(s). 
 
6.3.1.5 Normal Tissue Constraints 
Dose volume histograms (DVH) for target volumes and selected normal tissues will be generated. 
Normal tissues evaluated will include (depending upon anatomic level) spinal cord, cauda equina, 
and sacral nerves. 
DVHs to be generated, by tumor site: 
Table 8 
Normal Tissue Radiation Dose Constraints 
STRUCTURE 
DOSE 
SURFACE 
DOSE  
CENTER 
DOSE  
CONTRA 
LENGTH, 
VOLUME, AREA 
Cervical Cord 
67 GyRBE 
55 GyRBE 
50 GyRBE 
5 cm 
Thoracic/Lumbar 
Cord 
63 GyRBE 
54 GyRBE 
50 GyRBE 
5 cm 
Cauda Equina 
77.4 GyRBE* 
70.2 GyRBE 
70.2 GyRBE 
*adjacent to tumor 
Sacral Nerves 
77.4 GyRBE* 
77.4 GyRBE* 
77.4 GyRBE* 
*adjacent to tumor 
Skin Over Spine 
66 GyRBE 
 
 
 ≤ 100 cm2  
 
STRUCTURE 
DOSE  
Esophagus 
< 1/3 < 65 GyRBE; 2/3 < 55 GyRBE; whole volume ≤45  GyRBE 
Lungs 
V20 GyRBE < 1/3 
Heart 
1/3 ≤ 60 GyRBE; 2/3 ≤ 45 GyRBE; entire volume ≤ 30 GyRBE  
Small Bowel 
57.6 GyRBE for < 50% circumference over length < 10 cm; otherwise 50.4 
GyRBE for volumes ≤ 300 mL 
Colon 
≤ 66 GyRBE to < 1/3 of circumference over length of 5 cm 
Rectum 
Posterior 1/3 ≤ 77.4 GyRBE over 5 cm and ≤ 70.2 GyRBE over 8 cm 
Kidneys 
At least 2/3 of one kidney to receive < 20 GyRBE 
Liver 
≤ 50% volume > 25 GyRBE; ≤ 40% volume ≥ 30 GyRBE 
GyRBE = gray relative biological effectiveness; cm = centimeter; cm2 = square centimeter; mL = milliliter 
Source: data provided by Massachusetts General Hospital 
 
 
 
 
 

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Quality Assurance 
 
Dose Specification 
A minimal of 95% of the prescription dose should be prescribed to a minimum of 95% of target 
volume at each dose level. Deviations and reasons for deviation should be recorded. 
Radiation guidelines for treatment of metastases or recurrences with palliative intent: Palliative 
radiation given to metastases or recurrences at primary site may vary across institution. Details of 
dose, fractionation, and technique should be recorded. A minimum of 8 Gy x 1 (or biologic 
equivalent as described in Section 6.3.1.1)  should be used for palliation. Stereotactic body 
radiotherapy (SBRT) should follow standard guidelines for safety.   
Radiation to secondary non-target sites:  May be allowed if demonstrates progression and will be 
evaluated for RECIST 1.1 response. 
6.4 Accountability and Disposal 
Used (if allowed by institutional policy) and unused vials of all IMP need to be retained in a 
place with limited access until appropriate drug accountability has been performed. Drug 
accountability must be documented whenever the IMP is either prepared or administered.   
Bavarian Nordic will provide a Drug Accountability Log for recording receipt, dispensation, and 
destruction of IMP (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   
the designated drug depot, a vendor selected by Bavarian Nordic, or discarded according to local 
regulations. 
Destruction or return of IMP must be agreed upon with Bavarian Nordic and appropriately 
documented. Documentation should be reviewed and signed off by the pharmacist and Clinical 
Research Associate 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 designated drug depot or a vendor selected by Bavarian Nordic 
after prior consultation with Bavarian Nordic. 

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7 Blood Collection for Correlative Biomarker Studies (Exploratory) 
7.1 Collection of Blood Samples 
A total of 274mL blood will be taken for exploratory analyses from each patient during the trial. 
Blood samples will be collected from all enrolled patients as described in Section 1.5.  
1. Six green top sodium heparin tubes (10 mL volume) will be taken for PBMC preparation. 
2. One SST tube (8.5 mL volume) for serum preparation. 
7.2 Sample Analysis 
Testing will be performed at Bavarian Nordic (Munich). 
7.2.1 Analyses of PBMCs: 
1. 
Pre- and post-baseline PBMCs, separated by Ficoll-Hypaque density gradient 
separation, will be analyzed for antigen-specific immune responses. PBMCs will be 
stimulated in vitro with overlapping 15-mer peptide pools of control peptides and 
tumor antigen associated peptides e.g. Brachyury.  
2. 
Post-stimulation analyses of CD4 and CD8 T cells will involve the production of 
activation associated cytokines e.g. IFN-γ.  
3. 
PBMCs from selected patients may be analyzed for numbers/percentages in standard 
immune cell types (e.g. CD4 and CD8 T cells, natural killer [NK] cells, regulatory T 
cells, myeloid-derived suppressor cells, and dendritic cells) and their activation status.  
4. 
HLA typing will be performed on the most abundant PBMC sample for each patient. 
7.2.2 Analyses of Serum 
1. 
Sera will be analyzed pre- and post-baseline for changes in the amount of soluble 
factors e.g. sCD27, sCD40 ligand 
2. 
Selected patients may be analyzed for antibodies to human tumor antigens e.g. 
Brachyury, carcinoembryonic antigen or MUC1. 
7.2.3 Collection, Processing, and Testing of Biomarker Samples 
A United States-based central laboratory will be responsible for distribution of sample collection 
kits as well as for collecting, processing and storage of samples as well as for sample 
management.  
Serum samples will be processed, aliquoted and interim-stored at the clinical sites and shipped to 
the central laboratory at the end of the collection phase.  

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Fresh Blood samples for PBMC purification have to be shipped priority overnight on the day of 
blood draw to the central laboratory for processing on the next day.  
All samples and aliquots generated will contain labels having the clinical trial protocol and a 
unique sample identification number.  
All samples will be pseudonymized, only the patient number will be provided by the clinical sites 
to the central laboratory.  
Exploratory Biomarker analyses will be done at:  
 
 
Bavarian Nordic GmbH 
 
 
 
In addition, a Clinical Research Organization may be selected to perform specific analyses.   
7.3 Future Use of Lab Specimens 
Specimens remaining after completion of all immunogenicity testing for the trial will be stored 
for future analysis supporting the licensure path of BN-Brachyury. Patients 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  
8.1 Definitions 
8.1.1 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial (starting with the signature of the informed consent form), whether or 
not the event is considered related to the treatment or clinically significant. For this trial, AEs will 
include events reported by the patient, as well as clinically significant abnormal findings on 
physical examination or laboratory evaluation. A new illness, symptom, sign or clinically 
significant laboratory abnormality or worsening of a pre-existing condition or abnormality is 
considered an AE.  All AEs must be recorded on the AE case report form.   
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until satisfactory resolution. AEs should be reported up to 30 days 
following the last dose of trial drug.    

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An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
• 
Results in discontinuation from the trial 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator 
will provide details about the action taken with respect to the test drug and about the 
patient’s outcome. 
8.1.2 Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of Investigational New Drug application 
safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
8.1.3 Unexpected Adverse Reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
8.1.4 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following serious criteria: 
• 
Death (with the exception of death due to progression of underlying malignancy). 
• 
A life-threatening adverse drug experience (any adverse event or suspected adverse 
reaction that places the patient or patient, in the view of the investigator or sponsor, at 
immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction 
that had it occurred in a more severe form, might have caused death). 
• 
Inpatient hospitalization or prolongation of existing hospitalization, with the exception of 
the following 

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o Hospitalization for planned surgery or procedure. 
o A visit to the emergency room or other hospital department < 24 hours and/or that 
does not result in admission.  
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug event when, based upon 
appropriate medical judgment, they may jeopardize the patient or patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
• 
Other Cancer (with the exception of non-melanoma skin cancer). 
• 
Transmission of Infectious Agent (e.g. pathogenic or nonpathogenic) via the trial 
vaccine(s). 
• 
Overdose (accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important). 
• 
In addition, any Adverse Event of Special Interest (AESI) will be reported in the same 
fashion as an SAE regardless if serious criteria have been met. 
8.1.5 Adverse Event of Special Interest 
For the purposes of this trial any Immune-Mediated Adverse Event (i.e. auto-immune diseases 
and immune-mediated clinical syndromes) occurring since first exposure to MVA-BN-
Brachyury, will be treated as an AESI. 
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 deserves close vigilance. 
8.1.6 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the Institutional Review Board (IRB)-approved 
research protocol and informed consent document; Investigator’s Brochure or other trial 
documents, and 
(b) the characteristics of the patient population being studied; AND 
• Is related or possibly related to participation in the research; AND 

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• Suggests that the research places patients or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
9 Assessments and Trial Procedures 
9.1 Medical History 
Clinically relevant Medical history occurring prior to signing of Informed Consent Form (ICF) 
should be collected. Special attention should be paid to any history of vaccine allergies. When 
reporting SAEs, medical history considered relevant to the reported SAE should be indicated 
within the SAE report. Additionally, any ongoing concomitant medications started prior to ICF 
signing should have the indication reported as medical history.   
9.2 Prior and Concomitant Medication 
All non-cancer treatment prior and concomitant medications taken in the 90 days prior to the 
screening visit will be captured. Prior cancer treatments will be captured indefinitely. In regards 
to SAE reporting: Any clinically relevant concomitant medication taken within 30 days prior to 
the onset of an SAE must be indicated as such within the SAE report. Any medications taken in 
response to the SAE are considered treatment medications, within the context of SAE reporting, 
and should also be indicated as such within the SAE report. 
Anti-emetics and antidiarrheal agents may be administered as required, but are not anticipated to 
be needed and should not be used prophylactically. Selection of the specific antiemetic regimen is 
at the discretion of the treating physician. Antiemetic regimens should not include 
dexamethasone or other steroids. 
Toxicities thought to be autoimmune related and attributable to vaccine would lead to 
discontinuation of vaccine and symptomatic treatment. This may also include the use of immune 
suppressive treatments such as glucocorticoids and replacement hormones if indicated. 
Other supportive care with blood components, antibiotics, analgesics, general medical therapy, 
etc., will be delivered as required. Any patients taking antibiotics for any reason must complete 
that course of therapy and be free of evidence of further infection before receiving any dose of 
vaccine. 
Live, attenuated vaccine including influenza vaccine (FluMist), are not allowed within 4 weeks of 
Day 1 and throughout the trial. 
Symptomatic anemia should be treated with appropriate red blood cell or erythropoietin support. 
Other investigational therapies will not be allowed while a patient participates in this trial. 

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No additional therapies, besides those dictated by the trial (vaccine and radiotherapy), to treat 
chordoma are allowed on trial. In the case of progression of a non-target lesion, local therapeutic 
interventions are allowed on protocol, including surgery or radiation. In these cases, the primary 
target lesion is still the only target to be used for assessment of efficacy. Interventions to other 
sites are allowed to provide treatment alternatives for patients while they remain on trial to 
evaluate the results of the experimental treatment.  
9.3 Physical Examination and Medical Assessment 
A complete physical examination will be performed at Screening/ Baseline visit. 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 the heart and lungs to check specifically for signs 
of any heart condition will be performed. The medical assessment is included in the physical 
examination see Section 1.5 for a detailed list of medical assessments required. Complete 
physical exams may be performed at visits other than those indicated based on investigator’s 
discretion. The Medical assessment will be completed at each visit. 
9.3.1 Safety Laboratory Measurements 
Safety laboratory parameters to be evaluated are: 
CBC/differential with platelet count 
Red blood cell count, hemoglobin, total and differential white blood cell count and platelet count.  
Hematocrit, mean corpuscular/cell volume, mean corpuscular/cellular hemoglobin, mean 
corpuscular hemoglobin concentration and red blood cell distribution width are routinely 
performed as part of the complete blood cell count and will be included in the laboratory report.  
Serum chemistry 
Na+, K+, Cl–, CO2, glucose, (BUN), creatinine, albumin, alkaline phosphatase, ALT, AST, total 
bilirubin, TSH (optional post screening, calcium, and ANA.  
TBNK 
This test measures percentages and absolute numbers of lymphocytes, CD3 T cells, CD4 T cells 
and CD8 T cells and in lymphocyte subsets also B cells and NK cells. 
Pregnancy test 
A serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of Beta-HCG) 
will be conducted for all females of child-bearing potential (FOCBP) according to trial schedule. 
 

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Viral Panel 
Testing for HIV antibody, hepatitis B surface antigen, and hepatitis C antibody will be conducted 
within 6 months of initiating treatment to determine eligibility to participate in the clinical trial. 
Reporting of laboratory test abnormalities. 
All laboratory test results captured as part of the trial should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported as such. 
The following laboratory abnormalities should be documented and reported on the AE (eCRF) 
and SAE reporting form, if appropriate: 
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory abnormality that required the patient to have trial drug discontinued or 
interrupted 
• Any laboratory abnormality that required the patient to receive specific corrective 
therapy.  
9.4 CT Scan 
A CT scan of the thorax, abdomen and pelvis will be done as described in Section 1.5 to assess 
tumor response. Screening scans are only acceptable if they are acquired within 28 days of the 
first dose. CT scans acquired during the treatment period have an allowable clinic visit window 
of ± 1 week. Image consistency is essential to allow comparisons of scans over time. At each site 
the same equipment and scanning parameters should be used throughout the trial. IV contrast is 
recommended except in cases where it is medically contraindicated.  
9.5 Reporting  
9.5.1 Collecting and Recording Adverse Events 
The Investigator will monitor the occurrence of adverse events for each patient during the course 
of the trial. All AEs (as defined above) reported by the patient, observed by the Investigator, or 
documented in medical records will be listed on the AE-section of the eCRF, whether believed by 
the Investigator to be related or unrelated to the trial vaccine. 
All AEs must be reviewed, graded and causality determined by an Investigator listed on the form 
FDA 1572 at the research center reporting the event(s). Collection of adverse events begins at the 
time the patient signs informed consent and continues until the final Post-Treatment Follow-up 
Visit. 
Adverse event terms should be recorded concisely, using acceptable medical terms. When 
possible, a diagnosis (i.e., disease or syndrome) rather than the component signs and symptoms 

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should be recorded on the eCRF (e.g., congestive heart failure rather than dyspnea, rales, and 
cyanosis). However, signs and symptoms considered unrelated to syndromes or diseases are to be 
recorded as individual adverse events on the eCRF (e.g., if congestive heart failure and severe 
headache are observed at the same time, each event is to be recorded as an individual adverse 
event). Only abnormal laboratory values that result in clinical sequelae or require medication for 
treatment should be recorded as an adverse event. The adverse event should not be recorded as a 
procedure or clinical measurement (i.e., a laboratory or vital sign). The underlying reason for the 
procedure or the abnormal clinical measurements, and, whenever possible, a diagnosis, should be 
recorded. The diagnosis should be recorded; not the individual lab test name.  
9.5.2 Reporting of SAEs 
Any SAE that occurs after the patient signs informed consent and until 30 days following 
administration of the last dose of trial product, irrespective of the treatment received by the 
patient, must be reported to BN within 24 hours of the investigative site learning of the event. All 
SAEs (initial and Follow-up information) will be reported to BN within 24 hours of the discovery 
of the event or information. SAE report forms will be available in electronic format as part of the 
eCRF. Manual, paper-based SAE report forms will be available as a backup process for the case 
of failure of electronic systems. BN or designee may request Follow-up and other additional 
information from the Investigator (e.g., hospital admission/discharge notes and laboratory 
results). Discharge summary at minimum will be requested for any hospitalization. 
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 patient 
• Involved trial medication/vaccine 
• AE(s) 
• Seriousness criterion  
• Date of onset 
• Investigator assessment of causality 
If trial drug vaccine is discontinued because of an SAE, this information must be included in the 
SAE report. 
Investigators must report SAEs to their governing IRBs in writing as soon as possible and in 
accordance with national and local laws and regulations. 
Periodic reporting is the responsibility of BN. 

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9.5.3 Reporting of AESIs 
All AESIs occurring throughout the specified reporting period, must be recorded on both the AE 
eCRF and immune-mediated reactions eCRF. AESIs must be reported in the eCRF immediately 
after detection.  
The reporting process and timelines for AESIs are identical to the SAE reporting process as 
described in Section 9.5.2 with the exception that AESIs are only to be reported if occurring since 
first exposure to MVA-BN-Brachyury. 
9.5.4 Reporting of Pregnancies 
IMP exposed pregnancies cannot be excluded with certainty. Patients who become pregnant prior 
to the first vaccination will be excluded from the trial and are regarded as screen failures. Patients 
who become pregnant during the active trial period (up to and including 30 days after receiving a 
dose of vaccine) must not receive additional doses of vaccine 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 IMP (either through maternal exposure or transmission of a medicinal 
product via semen following paternal exposure), should be followed-up until delivery in order to 
collect information on the outcome of the pregnancy. 
Patients 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 vaccine dose. 
If a patient becomes pregnant during the active trial period (up to and including one month 
[minimum 30 days] after receiving a dose of vaccine), this must be reported to BN on a manual 
Pregnancy Report Form (available in the Site Reference Manual and in electronic fillable format) 
within 24 hours of the investigator’s becoming aware of the event.  
Female patients or female partners of male patients will be counseled as to any possible known 
risks to either the partner or the child. 
A pregnancy should be followed to term, 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. 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. 
However, hospitalization for delivery is a prospectively planned hospitalization and is not 
considered a SAE per se. Pregnancies resulting in an abnormal outcome (e.g., congenital 
abnormality, birth defect, or infant death) should be reported as SAEs within 24 hours of the 
investigator becoming aware of the event. 

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9.5.5 Progression of Underlying Malignancy 
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 
SAE. However, clinical symptoms of progression should be reported as (S)AEs if they cannot be 
determined to be exclusively due to the progression. 
All deaths should be reported with the primary cause of death as the AE 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 
10 Statistical Considerations  
10.1 Primary Trial Hypothesis 
This is a single arm 2-stage Phase 2 clinical trial based on Simon 2-stage optimal design (Simon, 
1989). The goal is to demonstrate that BN-Brachyury plus radiation therapy can induce objective 
radiographic responses in patients with advanced chordoma. Full details of planned analyses will 
be described in a separate Statistical Analysis Plan document. 
10.2 Endpoints 
Primary endpoints:  
• 
ORR anytime within 12 months post completion of radiation on target lesion(s) based on 
modified RECIST 1.1. Refer to Section 10.5 for the response criteria. 
Secondary efficacy endpoints: 
• 
PFS by modified RECIST 1.1 
• 
Improvement in clinical symptoms measured by the BPI-SF 
Safety endpoints: 
• 
Injection site reaction 
• 
Other adverse events 
• 
Changes in chemistry and hematology laboratory values 
 
 
 
 

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Exploratory endpoints: 
• 
ORR anytime post completion of radiation on all lesions by standard RECIST 1.1 
• 
ORR anytime within 12 months post completion of radiation on target lesion(s) based on 
Choi (Choi, 2007) criteria and volumetric criteria 
• 
PFS based on all lesions by standard RECIST 1.1 
• 
PFS based on target lesion(s) by Choi (Choi, 2007) criteria and volumetric criteria 
10.3 Sample Size Consideration 
The null hypothesis that the true ORR anytime within 12 months post completion of radiation is 
5% will be tested based on a one-sided alternative. In the first stage, 10 patients will be accrued. 
If there are 0 responders in these 10 patients, the trial will be terminated. If there is at least 1 
responder in these 10 patients, 19 additional patients will be accrued for a total of 29 patients. 
The null hypothesis will be rejected if 4 or more responses are observed in 29 patients. This 
design retains a one-sided type I error rate of ≤0.05 and achieves 80% power when the true 
response rate is 20%. 
The optimal design minimizes the expected sample size under the null hypothesis while 
satisfying the type I error and power constraint. With the above design, the probability of early 
stopping is 60% and the expected sample size is 17.6 when the true response rate is 5% (under 
the null hypothesis). 
10.4 Trial Cohort/ Data Set to be Evaluated 
10.4.1 Analysis Sets 
For the purpose of statistical analysis, there are 2 analysis sets: the evaluable analysis set and the 
full analysis set (FAS). 
The evaluable analysis set consists of all patients who have completed the following: 
• 
Two prime doses of MVA-BN-Brachyury, and 
• 
One booster dose of FPV-Brachyury prior to radiation, and 
• 
Completed the radiation therapy, and 
• 
At least 3 out of 4 booster doses of FPV-Brachyury in 14 weeks after radiation, and 
• 
Have both baseline (defined as measurement prior to first prime dose of MVA-BN-
Brachyury), and at least one post-baseline CT or MRI scan for objective tumor evaluation. 
The primary analysis population for ORR anytime within 12 months post completion of radiation 
and secondary efficacy endpoints is the evaluable analysis set. Patients who failed to meet the 

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evaluable criteria will be replaced to retain the statistical power unless 4 or more responses have 
been observed or the number of responders will still be less than 4 even if all replacement 
patients would be responders. If there are more than 10 evaluable patients at the end of stage 1 
analysis or more than 29 evaluable patients at the end of stage 2 analysis, primary evaluation will 
be based on the first 10 accrued or first 29 accrued evaluable patients. Sensitivity analysis will 
include all evaluable patients if applicable.   
The FAS consists of all patients who have enrolled and received any dose of MVA-BN-
Brachyury or FPV-Brachyury. This is the primary analysis set for safety and immune response, 
and secondary analysis set for efficacy. 
10.4.2 Analysis Periods 
Safety data will be summarized overall and by the following analysis periods: 
• 
Prime vaccination period: from first dose of MVA-BN-Brachyury to start of radiotherapy 
• 
Radiation therapy period: from start of radiation therapy to resuming FPV-Brachyury 
injections. 
• 
Post radiation therapy booster vaccination period: from restart of FPV-Brachyury 
vaccination after radiation therapy to last injection of FPV-Brachyury plus 30 days. 
The treatment period is defined as from start of first dose of MVA-BN-Brachyury until 30 days 
after the last trial treatment (either radiation therapy, MVA-BN-Brachyury, or FPV-Brachyury). 
10.4.3 Timing of Analysis 
The first post treatment (vaccination plus radiation therapy) objective radiographic response 
assessment by the investigator will occur approximately 14 weeks after completion of radiation 
therapy. Therefore, the end of stage 1 analysis to make a go versus no-go decision by the BN 
team will occur when all of the first 10 patients accrued have completed at least two post-baseline 
CT or MRI scans for tumor assessment or the minimum threshold for stage 2 enrollment (at least 
1 objective response) has occurred. For patients who have completed multiple scans, the best 
objective response will be used. If at least one objective response is observed prior to the end of 
stage 1 analysis, enrollment of stage 2 patients will continue regardless of timing of the end of 
stage 1 analysis. 
The end of stage 2 analysis will occur after all of the patients accrued have completed at least two 
post-baseline CT or MRI scans for tumor assessment. Because objective radiographic response 
rate may increase with further follow up, the data may be analyzed with updates if subsequent 
follow up demonstrates increased objective response. For patients who have completed multiple 
scans, the best objective response will be used.  

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Final analysis will occur when all of the patients accrued have either completed the 2-year 
treatment period or have progressed. 
10.4.4 Subgroup Analysis 
Location of primary tumor: Sacral, Mobile Spine, or Clival 
Histologic Subtype: Classic and Chondroid. 
10.4.5 Efficacy Analysis 
10.4.5.1 Primary Efficacy Analysis 
ORR is defined as the proportion of patients with response (Complete Response [CR] + Partial 
Response [PR]) based on a modified RECIST 1.1 response criteria (refer to Section 10.5 for 
further details of the response criteria). The primary analysis population is the evaluable analysis 
set.   
ORR based on best post-treatment tumor assessment will be summarized overall, by location of 
primary tumor and by histologic subtype, and the 90% confidence interval will be computed. 
ORR will also be summarized by visit where tumor assessment is scheduled. Due to the discrete 
and conservative property of the exact (Clopper-Pearson) confidence limit, the Wilson score 
confidence limits will be used. The Wilson interval has been shown to have better performance 
than the Clopper-Pearson interval (Brown et al., 2001).  
10.4.5.2 Secondary Efficacy Analysis 
The primary analysis population for the secondary endpoints is the evaluable analysis set. 
Secondary analysis will also be performed on the FAS. 
PFS is defined as the time interval from first treatment of MVA-BN-Brachyury to objective 
tumor progression based on target lesion(s) or death whichever occurs first. Patients 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. The product-limit Kaplan-Meier curve will 
summarize PFS graphically. Median survival and their 95% confidence intervals will be 
computed. Progression-free rates will be summarized by visit where scheduled tumor assessment 
is performed, along with their Wilson score confidence intervals. 
PFS per modified RECIST 1.1 based on the investigator’s assessment will be used as one of 
the two secondary efficacy endpoints.  The immune- related radiographic response modification 
requires a confirmation of progressive disease (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.  

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The BPI-SF will be scored as follows: 
• 
Pain intensity Worst, Least, Average in the last week and pain intensity Right now as 
recorded in eCRF. 
• 
Composite pain severity score (a mean severity score of the above four pain items) 
• 
Composite pain interference score (a mean of the seven interference items). This will be 
calculated if at least four of the seven interference items have been completed on a given 
administration. Otherwise, the pain interference score will be considered missing. 
Summaries for BPI-SF will be provided by study period and include continuous summary 
statistics.   
10.4.5.3 Exploratory Analyses 
Analyses of biomarker exploratory endpoints will be based on the FAS where at least one post-
baseline and the baseline assessment is available. Missing data will not be imputed. Analyses will 
focus on comparing the post-baseline value with the baseline value. Correlation between tumor 
response and immune responses will be explored. 
Continuous data will be summarized via mean, standard deviation, median, minimum, and 
maximum by visit where samples are collected per trial schedule. 95% confidence intervals of the 
mean will be computed. Log transformation of the data may be performed (e.g., ANA titer), and 
therefore the geometric mean and the 95% confidence interval will be summarized instead.   
For response rate and other categorical data, number and percentage will be summarized.   
For additional analyses of PFS, the following methods will be used: 
• 
PFS by the Choi response criteria based on target lesion(s): (Choi, 2007) During the course 
of immunotherapy, changes in tumor dimensions do not necessarily reflect tumor response. 
In the Choi (Choi, 2007) response criteria, progressive disease is defined as ≥10% increase 
in sum of longest diameters of lesions; does not meet the criteria for partial response by 
virtue of tumor attenuation, new intratumoral nodules, or an increase in the size of the 
existing intratumoral modules. 
• 
PFS based on target lesion(s) by volumetric segmentation (Fenerty et al., 2016) 
• 
PFS based on all lesions by standard RECIST 1.1 
 
ORR analysis using standard RECIST 1.1 based on all lesions, using the Choi (Choi, 2007) and 
volumetric criteria (Fenerty et al., 2016) based on target lesion(s) per external radiological review 
will be performed similar to the primary analysis. 

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10.4.6 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 9.5 of this protocol.   
Safety will be evaluated by the incidence of injection site reaction Treatment-Emergent Adverse 
Events (TEAEs) and SAEs, and laboratory abnormalities based on the Safety Population, and 
will also be evaluated by location of primary tumor. 
A TEAE is an adverse event with an onset on or after initiation of trial treatment, or an adverse 
event present at initiation of trial treatment that worsens (i.e., increase in severity: On-Study 
Grade > Baseline Grade); or relationship to trial treatment is reported as a possible, probable, or 
definite. Verbatim descriptions of TEAEs will be mapped to Medical Dictionary for Regulatory 
Affairs Version 18 or newer and graded according to NCI-CTCAE, Version 4.03 or newer. All 
TEAEs occurring from the first dose through 30 days of last dose of trial product, if unrelated to 
trial treatment or non-serious, and all trial treatment related serious adverse events and AESIs 
through 30 days of last dose of trial product, will be collected and will be summarized by analysis 
period, system organ class, and preferred term and further by NCI-CTCAE grade.  
Laboratory toxicities will be defined based on universal normal ranges and NCI-CTCAE, 
Version 4.03 or newer. The number and percentage of patients will be summarized by grade 
using the most severe grade by analysis period.  
10.5 Response Criteria 
RECIST version 1.1 will be used for radiographic assessment. However, at investigator 
discretion, immune-related radiographic response criteria principles can be used. If a patient has 
enlargement of his/her target lesion at the first restaging scan after completion of radiotherapy, 
he/she may remain on trial until confirmation of progression on a subsequent scan (at least 
4 weeks later). Similarly, any response must also be confirmed with a repeat scan at least 4 weeks 
later.  
For the primary and secondary RECIST-based endpoints, a modified RECIST 1.1 assessment 
(based on targeted radiated lesion(s)) will be used. Progression of a non-target lesion does not 
result in disease progression by the modified RECIST evaluation we will use for this trial. The 
purpose of the trial is to determine if radiation plus vaccine can shrink the irradiated tumor. In 
these cases, local interventions may be considered to other non-target lesions (surgery, radiation, 
or ablation) at the investigator’s discretion. If a patient must come off trial due to non-target 
lesion progression, he/she may be replaced with another patient to ensure statistical power is 
maintained for the primary analysis. 

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The primary target lesion (the lesion that is selected prior to initiation of therapy) will be 
measured by RECIST techniques using a modified RECIST 1.1 (only focused on the target lesion 
for evaluation of the primary endpoint) at baseline. This lesion will be the target that is irradiated. 
In some cases, if more than one lesion can be irradiated; multiple target lesions may be selected. 
Only those that receive adequate radiotherapy will be considered target lesions for RECIST 
assessment and primary endpoint analysis.  
All patients in this trial must be assessed for response to treatment, even if there are major 
treatment deviations. If a patient has not completed adequate treatment to be evaluated for 
response to treatment, he/she should still be assessed, but he/she may be replaced to maintain 
statistical power. The primary endpoint assessment of ORR anytime within 12 months post 
completion of radiation will be based on the response to adequate treatment, which will require 
vaccination and completion of adequate radiotherapy. Progression prior to that point will not be 
considered treatment failure for purposes of primary endpoint analysis.  
Standard RECIST 1.1 evaluations based on all lesions will be performed by external radiological 
reviewers and results will be included in exploratory analyses. 
Each patient will be assigned one of the following categories: 1) CR; 2) PR; 3) SD; 
4) progressive disease; and 5) not evaluable (death prior to restaging from malignant disease, 
toxicity, or due to other causes; or insufficient data). Patients will be assessed at fixed intervals as 
indicated by the schedule of events (Section 1.5). 
10.6 Toxicity Criteria 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the trial. The descriptions and grading scales found in the revised NCI-CTCAE 
version 4.03 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the NCI-CTCAE version 4.03. A copy of the NCI-CTCAE version 4.03 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov).   
11 Ethical Aspects 
11.1 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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11.2 Approval by an Institutional Review Board / Independent Ethics Committee 
Before enrollment of patients 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 or Independent Ethics Committee (IEC). Amendments to the 
protocol will be patient to the same requirements as the original protocol. 
The Investigator will submit a progress report at least once yearly to the IRB or IEC. However, 
the frequency of these reports will depend on IRB or IEC requirements. As soon as possible after 
completion or termination of the trial, the Investigator will submit a final report to the IRB or IEC 
per the IRB or IEC 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 or IEC local requirements, and in compliance with FDA regulations and ICH GCPs. 
Copies of all correspondence between the investigator and the IEC/IRB must be forwarded 
immediately to the Sponsor. In case of withdrawal of IEC/IRB approval of the trial, the Sponsor 
has to be contacted immediately by facsimile, e-mail or telephone. 
11.3 Confidentiality and Data Protection 
Information on maintaining patient confidentiality in accordance with individual local and 
national patient privacy regulations must be provided to each patient as part of the informed 
consent process either as part of the informed consent form 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 patient that for the evaluation of trial results, 
the patient’s protected health information (PHI) obtained during the trial may be shared with BN 
and its designees, regulatory agencies, and IRBs/IECs. As the trial Sponsor, BN will not use the 
patient’s PHI or disclose it to a third party without applicable patient authorization. It is the 
Investigator’s or designee’s responsibility to obtain written permission to use PHI from each 
patient. If a patient withdraws permission to use PHI, it is the Investigator’s responsibility to 
obtain the withdrawal request in writing from the patient and to ensure that no further data will be 
collected from the patient. Any data collected on the patient 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 
patient will be respected with strict adherence to professional standards and regulations. 

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12 Informed Consent and Assent 
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the trial, including answering any questions the patient may have 
throughout the trial and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial. 
No patient can participate in the trial without first having given informed consent or assent in 
writing. The investigator or his delegate will inform the patient 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 patient will also be informed 
of the potential future use of biological samples collected during the trial.  
ICF or assent will be used to explain to the patient in simple terms the potential risks and benefits 
of trial participation and to document that the patient 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 or assent to participate in the 
trial is given by each patient (or their legal representative). This includes obtaining the 
appropriate signatures and dates on the ICF or assent prior to the performance of any protocol 
procedures and prior to the administration of trial drug. 
One signed copy of the Informed Consent or assent (including HIPAA) must be given to each 
patient 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. 
Patients 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. 
Patients also provide consent or assent 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 patient’s PHI 
will be maintained. 
The Informed Consent and assent will be prepared in accordance with ICH GCP guidelines and 
must be approved by the appropriate IRB. 

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13 eCRF and Retention of Records 
Patient data will be entered into BN-approved eCRFs in a validated electronic data capture 
database, transmitted electronically to BN and combined with data transmitted from other 
external systems (e.g. lab data). All data transmissions will be secure. Personal identifiers will not 
be used when collecting and storing data. 
BN Data Management will utilize applicable BN standards and data cleaning procedures with the 
objective of identifying any inconsistencies in the data and querying the site for resolution of 
discrepancies. Adverse events, medical history and concomitant medications will be coded 
utilizing Medical Dictionary for Regulatory Affairs and World Health Organization Drug 
dictionaries. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI. During the trial, the PI must maintain complete and accurate documentation for the 
trial. The PI is responsible to ensure the accuracy, completeness, and timeliness of the data 
reported. 
13.1 Electronic Case Report Form (eCRF) 
eCRFs will be used to collect the clinical trial data and must be completed for each enrolled 
patient. All data should be accurately recorded such that the information matches the data 
contained in patient’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 eCRFs designed for this trial 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 patient’s visit. At all times, the 
Investigator has final responsibility for the accuracy and authenticity of all clinical data. 
The eCRFs exists within an electronic data capture (EDC) system with controlled access 
managed by the Sponsor or its authorized representative for this trial. Trial staff will be 
appropriately trained in the use of 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. 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 patient data (e.g., paper, CD-ROM or other appropriate 
media) for archiving at the clinical trial site. 
13.2 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 

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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.  
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. 
13.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol. The noncompliance 
may be either on the part of the participant, the investigator, or the trial site staff. As a result of 
deviations, corrective actions are to be developed by the site and implemented promptly.  
The PI or designee will be responsible for identifying and recording all deviations which are 
defined as isolated occurrences involving a procedure that did not follow the protocol or a 
protocol-specific procedure. All deviations from the protocol and actions taken will be recorded 
in the source data and placed in the trial specific regulatory file. Protocol deviations must be sent 
to the local IRB per their guidelines. The site PI/trial staff is responsible for knowing and 
adhering to their IRB requirements. Further details about the handling of protocol deviations will 
be included in the site reference manual. 
14 Monitoring of the Trial 
Representatives of BN or its designee will monitor this trial until completion. Monitoring will be 
conducted according to the monitoring plan. The monitoring plan will specify in detail the items 
for source data verification and other tasks, to be performed by the Clinical Research Associate 
during the clinical trial site visit. 

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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, 
Standard Operating Procedures, and other written instructions and regulatory guidelines, and to 
ensure the quality and integrity of the data. This trial is also patient 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 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 patients during this clinical trial. 
However, because of the experimental nature of this treatment, the Investigator agrees to allow 
the IRB/IEC, representatives of BN, its designated agents and authorized employees of the 
appropriate Regulatory Authority (e.g., FDA) to inspect the facilities used in this clinical trial 
and, for purposes of verification, allow direct access to the hospital or clinic records of all 
enrolled patients. A statement to this effect will be included in the informed consent and 
permission form authorizing the use of protected health information. 
15 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. All trial -related documentation must be made 
available to the designated auditor. In addition, representatives from local, state, or federal 
regulatory authorities (e.g., FDA) may choose to inspect a trial site at any time before, during, or 
after completion of the clinical trial. 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 by the 
Regulatory Authority for verification, audit, or inspection purposes.  
16 Responsibility of the Investigator 
The 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 aspects (see 
Section 11). 
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 patient information has to be changed accordingly.  
It is the responsibility of the investigator to ensure that the eCRF is completed in a timely manner 
following each patient’s visit and that the signature page for the entire set of eCRFs is 
electronically signed at the conclusion of the trial as part of the site closure process. 

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At the conclusion of the trial and following consultation with BN and/or its’ representatives, the 
investigator will ensure that final disposition of IMP is properly managed, including supervision 
of the return and/or destruction of any unused product according to local legal requirements. 
The investigator may ask to terminate participation in the trial due to administrative or other 
reasons. If this should be the case, appropriate measures which safeguard the interests of the 
participating patients 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 E6 (R1) Guideline for GCP, Section 4.9, “Record and Report” and 
regulatory and institutional requirements for the protection of confidentiality of patients. 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 reviews, 
audits/inspections, 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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Appendix 1: 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 weeks 
confirmation**  
CR 
Non-CR/non-PD 
No 
PR 
> 4 weeks 
confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/non-
PD/not evaluated 
No 
PR 
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 
Any  
Any 
Yes 
PD 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 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. 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort 
should be made to document the objective progression even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the evaluation 
of complete response depends on this determination, it is recommended that the residual lesions be 
investigated (fine needle aspirate/biopsy) before confirming complete response status. 
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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Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as > 20 mm by chest x-ray, as > 10 mm by CT scan, or > 10 
mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be > 15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm). At baseline and follow-up, only the short axis will be measured and followed. 
Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 

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Evaluable Disease 
Disease that cannot be measured directly by the size of the tumor but can be evaluated by other 
methods. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
Non-Target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 
5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up. 
 
 
 

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Appendix 2: Eastern Cooperative Oncology Group Performance Status 
These scales and criteria are used by doctors and researchers to assess how a patient's disease is progressing, 
assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and 
prognosis. They are included here for health care professionals to access.  
 
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.  
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the scale, 
please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis M.D., Group 
Chair.