A Phase I Trial Evaluating a Mutanome-directed Immunotherapy in Patients With High Grade Serous Carcinoma (HGSC) of the Ovary, Fallopian Tube or Peritoneum.
Phase: PHASE1
Conditions: Ovarian Carcinoma, Fallopian Tube Cancer, Peritoneal Carcinoma
Sponsor: Transgene

 
 
 
 
 
Clinical Study Protocol 
 
CONFIDENTIAL 
 
A phase I trial evaluating a mutanome-directed immunotherapy in patients with high 
grade serous carcinoma (HGSC) of the ovary, fallopian tube or peritoneum who 
experience an asymptomatic relapse 
 
Study phase: I 
 
PROTOCOL N° TG4050.01 
Version 9.0 / 12 September 2023 
 
 
EudraCT N°: 2018-003266-14 
 
 
COORDINATING 
INVESTIGATOR:  
 
Matthew S. BLOCK, MD, PhD 
 
 
 
 
 
Mayo Clinic 
200 First Street SW 
Rochester MN 55905 
USA 
Phone : 
 
 
 
SPONSOR : 
Transgene  
Boulevard Gonthier d'Andernach 
Parc d'Innovation - CS80166 
67405 Illkirch Graffenstaden Cedex - FRANCE 
 
 
PERSON TO CONTACT:  
 
 
 
 
 
 
Clinical Project Manager 
 
 
 
 
 
Transgene   
 
 
 
 
 
The confidential information contained in this document is the property of Transgene. It is provided to you in confidence, for review by you, 
your staff, regulatory authorities, and members of ethics committees or institutional review boards. It is understood that this information will 
not be disclosed to any other third party, in any form, without prior authorization from Transgene, except to the extent necessary to obtain the 
written informed consent from the persons to whom the Investigational Medicinal Product may be administered. 
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Transgene / Confidential 
Study Protocol TG4050.01 
Final Version 9.0 – 12 SEP 2023 
Page 2/67 
 
INVESTIGATORS / STUDY ADMINISTRATIVE STRUCTURE 
NAMES AND CONTACT DETAILS 
Coordinating Investigator 
Matthew S. BLOCK, MD, PhD 
Mayo Clinic 
200 First Street SW 
Rochester MN 55905 
USA 
Phone:
 
 
Centers / Investigators 
The complete Investigators list is available in the Trial Master 
File at Transgene. 
 
 
Transgene’s Staff 
 
 
 
 
Chief Medical Officer 
Pharmacovigilance 
Physician 
Clinical Project Manager 
 
 
 
 
 
 
  
Clinical Development 
Transgene  
Boulevard Gonthier d'Andernach 
Parc d'Innovation - CS80166 
67405 Illkirch Graffenstaden Cedex - FRANCE 
Phone: 
 
Fax: +
 
 
Clinical Supplies Manager  
 
 
 
 
 
Clinical Trial Manager 
 
 
 
 
Statistician 
 
 
 
 
A complete list of details for the Contract Research Organization (CRO), the central 
laboratory/ies and the independent data monitoring committee(s) is available in the 
Investigator Site File and in Transgene files. 
During the study, if applicable, the administrative structure will be updated in the Investigator 
Site File and in Transgene files. 
 
 
 
 
 
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TG4050.01_PSPv9_RST
Unique ID: 652061746b07600042c859a1 v.2
Florence Document ID: 652061746b07600042c859a1 v.2
page: 1 of 2
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eSignature Addendum
All eSignatures below were executed using Florence
 21 CFR Part 11 compliant software for eSignatures
TG4050.01_PSPv9_RST
Unique ID: 652061746b07600042c859a1 v.2
Florence Document ID: 652061746b07600042c859a1 v.2
page: 2 of 2
Current Electronic Signatures (v.2): 
Signed electronically by: Matthew Block 
Date: 06-Oct-2023 @ 04:47 PM CDT
Reason: Acknowledge
Previous Electronic Signatures: 
There are no signatures for any previous versions.
PPD

Transgene / Confidential 
Study Protocol TG4050.01 
Final Version 9.0 – 12 SEP 2023 
Page 4/67 
 
SYNOPSIS 
Sponsor: Transgene 
IMP:  TG4050, an MVA based, mutanome-targeted individualized immunotherapy 
 
 
Study Title 
A phase I trial evaluating a mutanome-directed immunotherapy in patients with high grade serous 
carcinoma (HGSC) of the ovary, fallopian tube or peritoneum who experience an asymptomatic relapse 
Study N°:TG4050.01 
EudraCT N°: 2018-003266-14  
Coordinating / Principal Investigator: Matthew Block, Mayo Clinic, Rochester, USA 
 
Investigational Centers/Countries: USA (3 sites from Mayo Clinic) and France (3 sites) 
Study Period: Q4 2019-Q4 2024 
Clinical Phase: I 
Objectives 
Primary objective: to evaluate the safety and tolerability of multiple subcutaneous (SC) injections of a 
neoantigen-directed active immunotherapy (TG4050) in ovarian, fallopian or peritoneal HGSC patients 
with an asymptomatic relapse. 
 
Secondary objectives: to evaluate: 
- Failure to provide TG4050 
- Failure to treat with TG4050 
- CA-125 doubling time and half-life as appropriate, time to normalization and response 
according to Gynecological Cancer InterGroup (GCIG) criteria 
- Time to measurable relapse in Cohort A and Time to progression in Cohort B per RECIST 1.1 
- Tumor response by using RECIST 1.1 
 
Translational research endpoints: 
 
 
  
 
 
 
  
 
Methodology 
This is a multicenter, open-label, single arm phase I study evaluating TG4050, an individualized active 
immunotherapy which refers to a mutanome-directed immunotherapy based on a Modified Vaccinia virus 
Ankara (MVA) vaccine specifically designed to target tumor-specific antigens identified in each ovarian, 
fallopian or peritoneal HGSC patient with an asymptomatic relapse. 
 
The study will consist of 2 parts for each patient: 
- 
A screening period starting at least 6 months after completion of standard first-line treatment including 
a platinum-based chemotherapy in patients with high risk serous fallopian, peritoneal or ovarian cancer 
who underwent cytoreductive surgery and achieved clinical complete response after platinum-based 
chemotherapy as demonstrated by non-evidence of disease on the last CT-scan and normal CA-125. 
High risk is defined by high grade and stage IIIC or stage IV disease. For each of those patients, an 
individualized, mutanome-directed immunotherapy TG4050 will be assembled. 
CCI

Transgene / Confidential 
Study Protocol TG4050.01 
Final Version 9.0 – 12 SEP 2023 
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Sponsor: Transgene 
IMP:  TG4050, an MVA based, mutanome-targeted individualized immunotherapy 
 
 
- 
A treatment period with TG4050 monotherapy starting in: 
o Cohort A: when patients develop an asymptomatic relapse defined on the basis of progressive 
serial elevations of serum CA-125 (GCIG criteria) or documentation of low volume 
radiological disease with CA-125 > Upper Limit of Normal (ULN). Low volume radiological 
disease is defined as radiologically visible disease excluding intra-hepatic or intra-splenic 
metastases, ascites or pleural effusion thought to require drainage 
o Cohort B: when patients develop an asymptomatic relapse with measurable disease excluding 
intra-hepatic or intra-splenic metastases, ascites or pleural effusion thought to require 
drainage, whatever serum CA-125 level and for whom further treatment is not planned within 
2 months. Longest diameter on CT-scan must not exceed 2 cm for non-nodal lesions and 2.5 
cm in short axis for nodal lesions 
 
Patients will receive TG4050 up to a total of 20 injections or until disease progression justifying initiation 
of further treatment, unacceptable toxicity including occurrence of a dose-limiting toxicity, or patient 
withdrawal for any reason, whichever occurs first. 
 
A safety run-in phase will be conducted in the first 3 treated patients from Cohort A or B who will be 
observed during the 6 weeks after the first administration of TG4050. During this phase, each patient will 
be monitored for 4 weeks after the first injection of TG4050 before the next patient can be enrolled. 
Enrolment of the next patients will be allowed if none of the 3 patients has experienced during the six weeks 
run-in phase: 
- 
any grade ≥3 toxicity that is at least possibly related to TG4050, with the following exception: pre-
existing grade 2 fatigue at baseline that would worsen up to grade 3 
- 
any death 
The occurrence of any of those events will trigger a study hold. An evaluation of the cause of toxicity will 
be performed and corrective measures, if appropriate, will be proposed before recruitment in the study can 
be reinitiated. 
 
Beyond the safety run-in phase, a dose-limiting toxicity is defined as any treatment-emergent AE ≥3 
toxicity that is at least possibly related to TG4050, with the following exceptions: pre-existing grade 2 
fatigue at baseline that would worsen up to grade 3. 
 
In any case, patients experiencing a dose-limiting toxicity will discontinue study treatment permanently. 
 
An Independent Data Monitoring Committee (IDMC) will be set up for the purpose of reviewing patients’ 
safety data and the conduct of the study. 
The IDMC will meet at completion of the safety run-in phase to analyze and review the safety data of the 
first 3 patients from Cohort A or B. The IDMC will then recommend whether it is possible to pursue patient 
enrolment as per study protocol. In addition to the review of the first 3 patients, the IDMC will review 
safety data of all patients included every 3 months during the first year and every 6 months thereafter. 
Ad hoc meetings may be held upon necessity. 
 
 
 
 
 
 
 
 
 
 
 

Transgene / Confidential 
Study Protocol TG4050.01 
Final Version 9.0 – 12 SEP 2023 
Page 6/67 
 
Sponsor: Transgene 
IMP:  TG4050, an MVA based, mutanome-targeted individualized immunotherapy 
 
 
Graphical synopsis 
 
 
 
Number of Patients 
- 
Screening period: an approximate number of 60 patients will participate. 
- 
Treatment period:  
o Cohort A: at least 13 patients will be enrolled to allow sufficient number of patients 
evaluable for safety, efficacy and immunological analyses. 
o Cohort B: Number of patients included at the time of full accrual in Cohort A with a 
maximum of 10 patients. 
Inclusion criteria 
Screening period  
1- Signed written informed consent in accordance to ICH-GCP and national/local regulation before 
any protocol-related procedures that are not part of normal patient care. 
2- Female patients ≥ 18 years of age 
3- Histologically confirmed high grade, stage IIIC or stage IV (FIGO staging) serous ovarian, 
fallopian or primary peritoneal carcinoma with abnormal CA-125 at diagnosis 
4- Patients who have undergone primary debulking surgery or interval debulking surgery and 
completed a total of at least 5 cycles of taxane-platinum combination. Note: patients may have 
received concurrent or maintenance bevacizumab or a PARP inhibitor. 
5- Patients must have achieved a complete response to therapy, as demonstrated by no residual disease 
on most recent CT scan and normal CA-125.   
6- Patient who remains disease free at least 6 months from last prior dose of cytotoxic chemotherapy 
(maintenance therapy with bevacizumab or a PARP inhibitor is allowed). 
7- Available tumor tissue, banked from previous abdominal debulking surgery and/or from a core 
needle biopsy performed at diagnosis if the patient received neoadjuvant chemotherapy, and 
peripheral blood samples for exome and transcriptome sequencing. 
 
Treatment period 
8- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at treatment period 
initiation 
9- Patients who have developed an asymptomatic relapse as defined by 
o Cohort A: CA-125 ≥ 2 times ULN on 2 occasions at least 1 week apart (GCIG criteria) or 
low volume radiological disease and CA-125 > ULN. Low volume radiological disease is 
defined as radiologically visible disease excluding intra-hepatic or splenic metastases, ascites 
or pleural effusion thought to require drainage. 
o Cohort B: patient asymptomatic with measurable disease, excluding intra-hepatic or splenic 
metastases, ascites or pleural effusion thought to require drainage, whatever serum CA-125 
level and for whom further treatment is not planned within 2 months. Longest diameter on 
CT-scan must not exceed 2 cm for non-nodal lesions and 2.5 cm in short axis for nodal 
lesions. 

Transgene / Confidential 
Study Protocol TG4050.01 
Final Version 9.0 – 12 SEP 2023 
Page 7/67 
 
Sponsor: Transgene 
IMP:  TG4050, an MVA based, mutanome-targeted individualized immunotherapy 
 
 
10- Adequate hematological, hepatic and renal functions: 
• 
Hemoglobin ≥ 9.0 g/dL  
• 
Neutrophils count ≥ 1.5 x109/L  
• 
Lymphocytes count ≥ 0.9 x109/L 
• 
Platelets count  100 x109/L 
• 
Total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert’s syndrome) 
• 
Aspartate aminotransferase (AST)  2.5 x ULN  
• 
Calculated creatinine clearance  45 mL/min using the Cockroft & Gault formula or ≥ 
45 mL/min/1.73m² using other methods 
11- Patients who received standard maintenance therapy will stop before initiation of TG4050 
administration. A free-interval of at least 30 days will be respected before first dosing of TG4050 
except for PARP inhibitor (at least 14 days). 
Exclusion criteria 
Screening period 
1- Patient having received any cancer immunotherapy including cancer vaccines, any antibody/drug 
targeting T cell co-regulatory proteins such as anti-PD1, anti-PDL1 or anti-CTLA-4 
2- Patients with other active malignancy ≤ 3 years prior to registration except non-melanoma skin 
cancer, stage 0 in situ carcinoma and recent early stage papillary thyroid cancer. If there is an 
history of prior malignancy, patient must not be receiving other specific treatment for their cancer 
3- Patient post-organ transplantation, including allogeneic stem cell or bone marrow transplantation. 
History of blood transfusion within 3 weeks prior to study entry visit. 
4- Known history of positive testing for Human Immunodeficiency Virus (HIV) or known AIDS 
(Acquired Immune Deficiency Syndrome) 
5- Any known allergy or reaction to eggs or attributed to compounds of similar chemical or 
biological composition to therapeutic vaccines/immunotherapeutic products 
6- Positive serology for Hepatis C Virus (HCV) or positive serum Hepatitis B surface antigen 
(HBsAg) within 3 months prior to or at study entry (tests required) 
Treatment period 
7- Measurable disease associated with the appearance of symptoms justifying initiation of further 
treatment. 
8- Major surgery within 4 weeks prior to treatment start 
9- Treatment with another investigational agent within 30 days prior to TG4050 treatment initiation. 
10- Patients under chronic treatment with systemic corticosteroids or other immunosuppressive drugs 
for a period of at least 4 weeks and whose treatment was not stopped 2 weeks prior to TG4050 
treatment initiation planned date, with the exception of patients with adrenal insufficiency who 
may continue corticosteroids at physiological replacement dose, equivalent to ≤ 10 mg prednisone 
daily. Steroids with no or minimal systemic effect (topical, inhalation) are allowed. 
11- Vaccination for the prevention of infectious diseases with a live vaccine during the four-week 
period prior to TG4050 treatment initiation planned date. Furthermore, patients should not receive 
any live vaccine during the period of study treatment administration. 
12- Patient with any underlying medical condition, that in the opinion of the investigator, could make 
the patient inappropriate for entry into this study or interfere significantly with the proper 
assessment of safety or toxicity of the study treatment.  
13- Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric 
illness/social circumstances that could limit compliance with study requirements. 
14- History of myocardial infarction ≤ 6 months. 
 

Transgene / Confidential 
Study Protocol TG4050.01 
Final Version 9.0 – 12 SEP 2023 
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Sponsor: Transgene 
IMP:  TG4050, an MVA based, mutanome-targeted individualized immunotherapy 
 
 
IMP: Dose, Mode of Administration 
In this study, the Investigational Medicinal Product (IMP) is TG4050. 
• 
The IMP is an individualized MVA construct, mutanome-directed immunotherapy tailored to each 
patient and derived from a replication deficient strain of vaccinia virus (Modified Vaccinia virus 
Ankara, MVA).  
• 
The individualized TG4050 construct will be assembled for each patient during the screening period. 
Study treatment will be started when a patient develops an asymptomatic relapse.  
• 
Patients will receive subcutaneous (SC) injections of TG4050 at a dose of 1x108 PFU weekly for the 
first 6 weeks and then every 3 weeks up to a total of 20 injections unless disease progression justifying 
initiation of further treatment, unacceptable toxicity including occurrence of a dose-limiting toxicity, 
or patient withdrawal for any reason, whichever occurs first. 
 
Reference / Associated Therapy 
Permitted medicines and therapies: 
• Any medications that are considered necessary for the patients’ welfare and will not interfere with the 
trial medication may be given at investigator’s discretion. 
• 
The use of the following drugs will not be restricted during the course of the study: G-CSF, 
erythropoietin, antiemetics and analgesics. 
• Topical, ocular, intra-articular, intranasal and inhalational corticosteroids (with minimal systemic 
absorption) 
•  The use of systemic corticosteroids during the study is restricted as follows: for short term treatment 
(≤7 days) of allergic reactions, or for replacement for adrenal insufficiency at doses equivalent to ≤ 10 
mg prednisone daily. 
Non-permitted medicines and therapies during the study treatment period: 
• 
Immunosuppressive agents 
• 
Immunosuppressive doses of systemic corticosteroids per restrictions described above. 
• 
Any concurrent antineoplastic therapy 
• 
Any live vaccine for the prevention of infectious disease  
• 
Any other investigational agent 
Duration of Study Treatment  
TG4050 will be administered up to a total of 20 injections or until disease progression justifying initiation 
of further treatment, unacceptable toxicity including occurrence of a dose-limiting toxicity, or patient 
withdrawal for any reason whichever occurs first. 
 
Criteria for Evaluation 
Failure to provide rate 
The proportion of patients for whom TG4050 cannot be provided and the reason for not being able to 
provide the vaccine will be recorded. 
 
Failure to treat rate 
The proportion of patients who cannot receive TG4050 and the reason that prevents the patient from being 
treated will be recorded. 
 
Safety assessment 
The following evaluations will be performed: 
• 
Physical examination including vital signs, body weight and performance status every week for the first 
6 weeks and then every 3 weeks. 
• 
AEs and Serious Adverse Events (SAEs) will be reported and graded according to NCI CTCAE, version 
5 at each visit. 
• 
Laboratory investigations will be undertaken: 

Transgene / Confidential 
Study Protocol TG4050.01 
Final Version 9.0 – 12 SEP 2023 
Page 9/67 
 
Sponsor: Transgene 
IMP:  TG4050, an MVA based, mutanome-targeted individualized immunotherapy 
 
 
- 
Complete blood count (CBC) including Red Blood cells (RBC), White Blood cells (WBC) and 
differential, Hemoglobin (Hb) and platelets at baseline, every week up to week 6, then every 3 
weeks up to Month 6 (Day 190), thereafter every 12 weeks, and at the end of treatment visit. 
- 
Biochemistry analyses including: AST, ALT, alkaline phosphatases, total bilirubin, glucose, 
electrolytes (sodium, potassium, magnesium and bicarbonates), creatinine and creatinine clearance 
at baseline, every week up to week 6, then every 3 weeks up to Month 6 (Day 190), thereafter every 
12 weeks, and at the end of treatment visit. 
• 
ECG at baseline, every 3 weeks for the first 6 weeks and then every 6 weeks up to Day 169, thereafter 
every 12 weeks, and at the end of treatment visit.  
 
Efficacy assessment  
• 
CA-125 determined in an accredited central laboratory will be measured within 7 days prior to 
treatment initiation and then every 3 weeks throughout the treatment period. CA-125 doubling time and 
half-life as appropriate, time to normalization and response according to GCIG criteria will be assessed. 
• 
Tumor response will be evaluated by using RECIST 1.1. A CT-Scan of the pelvis and abdomen (or 
MRI) and X ray or preferably CT-scan of the chest will be performed within 21 days prior to treatment 
initiation, on Day 43 and then every 9 weeks. 
 
Immune responses 
Patient samples collection: 
• 
Cytapheresis for collection of PBMC will be performed prior to first treatment administration and 9 
weeks (D64) after treatment initiation. In case a patient is withdrawn prior to D64, a cytapheresis is to 
be performed at end of treatment visit. If the post-baseline cytapheresis is not clinically feasible, it can 
be replaced by a 150 ml blood draw. 
• 
Blood samples (prior to study treatment administration, when applicable) at baseline, on Day 8, Day 
22, Day 43, Day 64, Day 85, Day 211 and at the end of treatment visit for extraction of serum, plasma 
and PBMC for longitudinal monitoring of response. 
 
Blood samples will be collected to assess the following parameters: 
• 
Whole blood cell phenotype on fresh blood samples by multiparametric flow cytometry (FACS). 
Proposed assessments include counting and phenotyping of memory and naïve T cells, regulatory T 
cells, CD8 T cells, B cells, NK cells, innate like T cells as well as relevant activation markers  
• 
Quantification of immune related soluble factors, cytokines, antibody responses to neoantigens and 
virus 
• 
Peripheral Blood Mononuclear Cells (PBMC) from whole blood to assess specific cellular immune 
responses against neoantigens 
• 
HLA Genotyping (class I and II) 
• 
Circulating tumor and immune markers 
 
Tumor sample(s) will be collected to assess: 
• 
Density of tumor infiltrating lymphocytes (TILs) and phenotyping of the infiltrated cells (cell type and 
activation markers) (Immunoscoring) 
• 
PD-L1 and other relevant immune related factor expression by IHC assessment  
• 
Transcriptomic analysis of whole tumor and purified immune cell populations 
- 
Evaluation of tumor mutation load 
 
Statistical Methods: 
This is a phase I first-in-man study. No formal sample size calculation is planned. 
Descriptive statistics will be used to present patient demographic and baseline characteristics, as well as 
safety, efficacy and immune data. 

Transgene / Confidential 
Study Protocol TG4050.01 
Final Version 9.0 – 12 SEP 2023 
Page 10/67 
 
 
TABLE OF CONTENTS 
 
INVESTIGATORS / STUDY ADMINISTRATIVE STRUCTURE .................................................................. 2 
DOCUMENT APPROVAL ................................................................................................................................... 3 
SYNOPSIS .............................................................................................................................................................. 4 
TABLE OF CONTENTS ..................................................................................................................................... 10 
ABBREVIATIONS / DEFINITION OF TERMS ............................................................................................. 13 
1. 
INTRODUCTION .................................................................................................................................. 15 
1.1. 
Disease background ............................................................................................................. 15 
1.2. 
Study population rationale .................................................................................................. 15 
1.3. 
TG4050 background ............................................................................................................. 16 
1.4. 
Translational research rationale .......................................................................................... 17 
1.5. 
Summary of the overall benefits and risks .......................................................................... 18 
 
Expected benefits ............................................................................................................................ 18 
 
Potential risks ................................................................................................................................. 18 
 
Measures taken to mitigate the risks .............................................................................................. 19 
2. 
OBJECTIVES ........................................................................................................................................ 19 
2.1. 
Primary Objective................................................................................................................. 19 
2.2. 
Secondary objectives ........................................................................................................... 19 
2.3. 
Translational research .......................................................................................................... 19 
3. 
STUDY DESIGN .................................................................................................................................... 20 
3.1. 
Overall study design and plan description ........................................................................... 20 
3.2. 
Number of centers and patients ............................................................................................ 22 
3.3. 
Discussion of Study Design ................................................................................................. 22 
3.4. 
Dose and schedule selection ................................................................................................ 23 
4. 
STUDY POPULATION ........................................................................................................................ 24 
4.1. 
Inclusion criteria ................................................................................................................... 24 
Screening period ........................................................................................................................................... 24 
Treatment period: ......................................................................................................................................... 25 
4.2. 
Exclusion criteria .................................................................................................................. 26 
Screening period ........................................................................................................................................... 26 
Treatment period .......................................................................................................................................... 26 
4.3. 
Criteria for patient premature withdrawal .......................................................................... 27 
 
Premature withdrawal from the trial ............................................................................................. 27 
 
Withdrawal from study treatment period ....................................................................................... 27 
 
Replacement policy ........................................................................................................................ 27 
4.4. 
Definition of end of study .................................................................................................... 27 
5. 
REGISTRATION PROCEDURES ...................................................................................................... 28 
5.1. 
Screening period .................................................................................................................. 28 
5.2. 
Treatment period ................................................................................................................. 28 
6. 
STUDY VISITS AND PROCEDURES ................................................................................................ 28 
6.1. 
Screening period .................................................................................................................. 28 
 
Evaluation description ................................................................................................................... 28 
 
Study entry visit .............................................................................................................................. 30 
 
Follow-up visits in patients with Complete Response .................................................................... 30 
 
Asymptomatic relapse study visit ................................................................................................... 31 

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6.2. 
Treatment period ................................................................................................................. 31 
 
Evaluation description ................................................................................................................... 31 
 
Baseline visit .................................................................................................................................. 32 
 
Study visits during the treatment period ......................................................................................... 33 
 
End of treatment visit (+7 days) ..................................................................................................... 34 
 
Follow-up for secondary activity endpoints (+/- 7 days) ............................................................... 34 
 
Safety Follow-up visit (+ 14 days) ................................................................................................. 34 
7. 
TREATMENT PLAN FOR TREATMENT PERIOD ........................................................................ 35 
7.1. 
Investigational Medicinal Product (IMP) characteristics ..................................................... 35 
 
Manufacturing ................................................................................................................................ 35 
 
Packaging and labeling .................................................................................................................. 35 
 
Conditions of storage and use ........................................................................................................ 36 
 
Preparation and administration procedure .................................................................................... 36 
 
Disposal and destruction or return ................................................................................................ 37 
 
Supplier .......................................................................................................................................... 37 
7.2. 
Treatment duration ............................................................................................................. 37 
7.3. 
Treatment modification ....................................................................................................... 38 
7.4. 
Treatment compliance ......................................................................................................... 38 
 
Dispensing and accountability ....................................................................................................... 38 
 
Assessment of compliance .............................................................................................................. 38 
7.5. 
Concomitant medications .................................................................................................... 38 
 
Prohibited and/or restricted medications during study treatment.................................................. 38 
 
Permitted medications/therapies .................................................................................................... 39 
7.6. 
Medical care of patients after end of study......................................................................... 39 
8. 
EVALUATION ...................................................................................................................................... 39 
8.1. 
Evaluation of screen failure ................................................................................................. 39 
8.2. 
Evaluation during the treatment period .............................................................................. 39 
 
Efficacy evaluation ......................................................................................................................... 39 
 
Safety evaluation ............................................................................................................................ 40 
 
Serious Adverse Event / Serious Adverse Reaction / Suspected Unexpected  Serious Adverse 
Reaction notification .................................................................................................................................... 45 
 
Special situations ........................................................................................................................... 46 
 
Laboratory values, vital signs, physical findings and other safety data ......................................... 47 
 
Translational research and exploratory evaluations ..................................................................... 47 
9. 
STATISTICAL METHODS PLANNED AND SAMPLE SIZE ........................................................ 48 
9.1. 
Data sets analyzed ............................................................................................................... 48 
 
Screening period ............................................................................................................................ 48 
 
Treatment period ............................................................................................................................ 48 
9.2. 
Determination of sample size .............................................................................................. 49 
9.3. 
Study endpoint ..................................................................................................................... 49 
 
Primary endpoint ........................................................................................................................... 49 
 
Secondary endpoints ...................................................................................................................... 49 
 
Translational research ................................................................................................................... 49 
9.4. 
Statistical and analytical plans ............................................................................................. 50 
 
Safety analyses for the treatment period ........................................................................................ 50 
 
Efficacy analyses for the treatment period ..................................................................................... 51 
 
Translational research ................................................................................................................... 51 
9.5. 
Methods of analysis ............................................................................................................. 51 
 
General considerations .................................................................................................................. 51 
 
Disposition of patients .................................................................................................................... 51 
 
Demographic and baseline characteristics .................................................................................... 51 
 
Treatments ...................................................................................................................................... 52 
9.6. 
Protocol deviations .............................................................................................................. 52 
10. 
CHANGES IN THE CONDUCT OF THE STUDY ............................................................................ 52 

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10.1. 
Protocol amendments ......................................................................................................... 52 
10.2. 
Premature termination or suspension of the study ............................................................ 53 
11. 
ETHICAL CONSIDERATIONS .......................................................................................................... 54 
11.1. 
Independent Ethics Committee/Institutional Review Board ............................................... 54 
11.2. 
Informed consent ................................................................................................................. 54 
11.3. 
Confidentiality of patient data ............................................................................................. 54 
11.4. 
Independent Data Monitoring Committee .......................................................................... 55 
 Responsibilities of the Independent Data Monitoring Committee .................................................. 55 
 Safety reviews to investigators ....................................................................................................... 55 
12. 
REGULATORY CONSIDERATIONS ................................................................................................ 55 
12.1. 
Regulatory approval / authorization .................................................................................... 56 
12.2. 
Investigators’ obligations ..................................................................................................... 56 
12.3. 
Insurance .............................................................................................................................. 56 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 56 
13.1. 
Monitoring ........................................................................................................................... 56 
13.2. 
Audit and inspection ............................................................................................................ 57 
14. 
DATA HANDLING AND RECORD KEEPING ................................................................................ 57 
14.1. 
Source data and documents ................................................................................................ 57 
14.2. 
Case report forms ................................................................................................................ 58 
15. 
CLINICAL STUDY REPORT AND PUBLICATION ....................................................................... 58 
15.1. 
Clinical study report ............................................................................................................. 58 
15.2. 
Confidentiality of study data ................................................................................................ 59 
15.3. 
Publication policy ................................................................................................................. 59 
16. 
ARCHIVING .......................................................................................................................................... 59 
16.1. 
Investigator site file .............................................................................................................. 59 
16.2. 
Trial master file .................................................................................................................... 60 
17. 
APPENDICES ........................................................................................................................................ 61 
18. 
REFERENCES ....................................................................................................................................... 62 
 
 
 

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ABBREVIATIONS / DEFINITION OF TERMS 
 
ABBREVIATIONS 
MEANING OF ABBREVIATIONS IN DOCUMENT 
AE 
Adverse Event 
ALT 
Alanine amino-transferase (= SGOT) 
AR 
Adverse Reaction 
AST 
Aspartate amino-transferase (= SGPT) 
BRCA 1 & BRCA 2 
Breast Cancer 1 & Breast Cancer 2 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CR 
Complete Response 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating Tumor DNA 
CTL 
Cytotoxic T Lymphocytes 
D 
Day 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic acid  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
FACS 
Fluorescence-activated cell sorter 
GCIG 
Gynecologic Cancer InterGroup 
GCP 
Good Clinical Practice 
GMO 
Genetically Modified Organism 
GOG 
Gynecologic Oncology Group 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HGSC  
High Grade Serous Carcinoma 
HIV 
Human Immunodeficiency Virus 
HLA 
Histocompatibility Leukocyte Antigen 
IB 
Investigator’s brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICMJE 
IDMC 
International Committee of medicinal Journal Editors 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
M 
Month 
mL 
Milliliters 
MRI 
Magnetic Resonance Imaging 
MVA 
Modified Vaccinia virus of Ankara 
NCI-CTCAE 
National Cancer Institute’s Common Terminology Criteria for Adverse Events. 
Also referred as CTCAE in the text 
NK 
Natural Killer 
PBMC 
Peripheral Blood Mononuclear Cells 
PD-1 
Programmed Death-1 
PD-L1 
Programmed Death Ligand-1 
PFS 
Progression Free Survival 
PFU 
Plaque Forming Unit 
PS 
Performance Status 
RBC 
Red Blood Cells 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 

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SC 
Subcutaneous 
sd 
standard deviation 
SOC 
Standard of Care 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TSAs 
Tumor Specific Antigens 
TIL 
Tumor Infiltrating Lymphocytes 
TMF 
Trial Master File 
TCR 
T Cell Receptor 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
 
 

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1. INTRODUCTION 
1.1. Disease background 
After initial surgical diagnosis, staging and cytoreduction, the standard primary chemotherapy 
for women with advanced epithelial ovarian, fallopian or peritoneal primary cancer consists of 
taxane and a platinum salt in combination, usually carboplatin and paclitaxel. 
Despite the high response rate for front-line therapy with more than 70 % of patients achieving 
a clinical response, the majority of patients with advanced ovarian cancer will subsequently 
relapse. In the past 5 years, bevacizumab combined with front-line chemotherapy and then 
given in maintenance was shown to provide a statistically and clinically significant 
improvement in PFS (Burger R.A. et al., 2011; Perren T.J. et al., 2011). In the GOG-0218 
trial (Burger R.A. et al., 2011) which enrolled incompletely resected stage III and stage IV 
epithelial ovarian cancer and mostly grade 3 disease (71.2 %), median PFS was increased from 
10.3 months in the control arm to 14.1 months in the concomitant and maintenance 
bevacizumab arm. However, no statistically significant difference in OS was observed in the 
final study analysis (Burger R.A. et al., 2018). The development of several PARP inhibitors has 
been an important advance in the treatment of ovarian cancer. More recently, their use as 
maintenance therapy was approved based on PFS improvement in particular in patients with 
homologous recombination deficiency tumors (Pujade-Lauraine E. et al., 2017). Hence, there 
is still a clear unmet medical need and new treatment approaches are strongly awaited to 
improve the outcome of high-grade serous carcinoma (HGSC) of the ovary, fallopian tube and 
peritoneum. 
One potentially attractive approach is tumor mutanome directed immunotherapy since ovarian 
cancer may be recognized and attacked by the immune system. Tumor infiltrating T cells were 
detected and their presence was shown to correlate with improved clinical outcome in advanced 
ovarian cancer (Zhang L. et al., 2003). Stimulation of the immune system with a vaccine may 
provide an opportunity to leverage long-term anti-tumor immune response while maintaining 
an excellent safety profile. On a longer term, such approach can potentially constitute a medical 
option in an indication of high medical need. Moreover, studies have demonstrated that residual 
disease or remanence of micrometastasis is a major prognostic factor for clinical recurrence 
(Braun S. et al., 2001). Micrometastases are scattered cancer cells with relatively low rates of 
replication, which may explain the lack of efficacy of cytotoxic therapy but may constitute an 
ideal target for immune mediated response.  
1.2. Study population rationale 
Patients with ovarian, fallopian or peritoneal cancer in the context of minimal residual disease 
will be enrolled. These patients have achieved complete clinical response after surgery and 
standard platinum-based therapy and will be enrolled when rise in serum CA-125 predicts a 
slow disease recurrence. 
Indeed, despite the high response rate for front-line therapy the majority of patients with 
advanced ovarian cancer will subsequently relapse. A substantial number of patients develop a 
biochemical relapse based on increased CA-125 measurement without clinical symptoms which 
can be associated with a low volume disease on CT-scan. For this group of patients, no survival 
benefit has been demonstrated from early chemotherapy treatment which means that patients 
participating into the present study will not be deprived from their standard of care treatment. 
The median lead time between CA-125 rise and initiation of second-line chemotherapy for 
clinical recurrence was reported to be 4.8 months (Rustin G.J. et al., 2010). This might be 

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explained by the low rate of proliferation of cancer cells at this stage of the disease. 
Additionally, before biochemical relapse, tumor cells are scattered and may be accessible to 
immune intervention as immunosuppressive properties of the disease may be lower than what 
would be encountered in larger tumors.  
Tumor infiltrating T cells were detected and their presence was shown to correlate with 
improved clinical outcome in advanced ovarian cancer. (Zhang L. et al., 2003). Taken together 
these properties of tumor cells at this stage of the disease make them promising target for cell 
mediated immune anti-tumor reaction. 
The time interval from completion of chemotherapy will be at least 6 months since only patients 
with platinum sensitive relapse are eligible for the study. Although we recognize that the 
complex interplay between chemotherapy induced lymphopenia and chemotherapy, we 
consider that this time interval would presumably be sufficient for recovery of patients from 
immune-compromising effect of chemotherapy. In addition, patients are required not to have 
been treated with chronic systemic corticosteroids or other immunosuppressive drugs for a 
period of at least 4 weeks before study entry and up to 2 weeks prior to first TG4050 treatment 
administration. Other parameters reflecting immune status of the patient may be included in the 
protocol as appropriate based on the recent state of the art. 
The present feasibility and safety clinical trial is then conducted in high grade serous ovarian, 
fallopian or peritoneal cancer patients with platinum-sensitive asymptomatic relapse after 
debulking surgery followed by platinum-based therapy. 
1.3. TG4050 background 
TG4050 is an immunotherapeutic product manufactured specifically for a given patient based 
on identification of tumor specific somatic mutations. Briefly, tumor specific mutations 
expressed in the tumor tissue are detected by comparing the tumor and healthy tissue exomes 
by massively parallel sequencing; evidence of expression of identified mutation is obtained 
through sequencing of tumor cells transcriptome (RNAseq). Subconsequently, mutated 
sequences are used to design a synthetic gene and cloned in a modified vaccinia Ankara viral 
vector (Bendjama K. and Quemeneur E., 2017). 
The Modified Vaccinia virus Ankara (MVA) has been generated through serial passages in 
chicken embryo fibroblasts. It has been used safely and effectively for smallpox vaccination in 
more than a hundred thousand individuals. The MVA has lost the pathogenicity of its parental 
virus, the Chorioallantois Vaccinia virus Ankara, through alterations of its genome, i.e. 15% of 
genome loss. The virus is replication defective in human cells, ensuring its safety and 
tolerability for clinical use but replicative in avian cells. This feature enables the use of an egg-
based manufacturing process. It has served as an effective vector in previous attempts to 
develop viral-based immunotherapies, in particular, the vector has been used for the production 
of several Transgene’s IMPs tested in phase 1 and phase 2 clinical studies. The long track record 
of clinical use of the MVA demonstrates an excellent safety profile and is not associated with 
cardiac safety issues like with replicative vaccinia virus (Elizaga M.L. et al., 2013), 
(Zitzmann-Roth E.M. et al., 2015). 
The use of cancer specific immunogenicity has been validated through a wealth of evidence 
preclinically and clinically. Tumor infiltration with cytotoxic T cell has been long known as a 
factor of positive prognostic. More recently, molecular characterization of tumor tissues 
demonstrated that antigens arising from tumor specific mutations are the main targets of 

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cytotoxic T cells (Schumacher T.N. et al., 2015). Therapeutics stimulating the immune system 
has leveraged successfully activity of these cells by bypassing the propensity of tumors to 
escape immune control by inhibiting effector cells. Therapies such as immune checkpoint 
inhibitors (ICI) have yielded high clinical efficacy by inhibiting pathways used by the tumor to 
downregulate the immune response (e.g., PD-1/PD-L1). One downside in such approach is that 
it remains limited to a relatively reduced fraction of patients whose immune profile is 
compatible with such intervention. Indeed, ICI therapy implies that there is a pre-existing 
immune response in patients, yet, tumors are also known to be able to inhibit priming of a 
cellular response by various mechanisms. 
The strategy behind TG4050 is to use the natural sensitivity of the immune system to trigger a 
response against tumor specific antigens (TSAs), by priming the immune system outside of the 
tumor environment. This response may then lead to a cytotoxic activity of T cells and 
improvement of patient outcome. Potentially, such approach may be used synergistically with 
other immune modulators. 
In the present study, TG4050 IMP is designed based on samples collected prior to the adjuvant 
chemotherapy and the therapy is only administered at the time of biochemical progression. 
Given the well documented high genomic instability of ovarian serous carcinoma (Vollebergh 
M.A. et al., 2012), and the tendency of chemotherapeutic agents to induce somatic mutation 
(Gercel-Taylor C. et al., 2005), the relevance of administrating after chemotherapy a GTMP 
targeting mutations identified prior to the said chemotherapy may be questioned. The recent 
work by (Arend R.C. et al., 2018) studied the relationship between mutation load and 
neoadjuvant therapy in ovarian carcinoma. Results from molecular profiling of serous ovarian 
carcinoma in 19 patients demonstrate that while mutation load may be affected by 
chemotherapy, the vast majority of mutations detected before and after neoadjuvant 
chemotherapy were the same (O'Donnell T. et al., 2018). Additionally, recent studies 
document differences of mutational profile between primary and metastatic tumor. While there 
is a significant evolution of the mutational landscape, on average 61% of mutations present in 
the primary tumor are found in a metastatic lesion (Masoodi T. et al., 2020). This suggests that 
while new mutations may be induced by treatment or natural evolution of the disease, mutations 
that appeared earlier in the history of the disease are likely to be conserved. Also, the use of up 
to 30 epitope targets mitigate the risk of loss of immune escape. In order to validate this 
assumption, the genomic profile of tumors will be studied at recurrence. 
1.4. Translational research rationale  
Besides the assessment of safety and tolerability, the current study is intended to provide critical 
data on the mechanism of action of TG4050. We aim at generating data that may help validating 
TG4050 as an effective tool for the development of tumor specific immune responses and obtain 
preliminary data on the antitumor efficacy of this individualized therapy. 
Material banked at diagnosis or after surgery will be used to identify tumor specific mutations 
and evaluate level of expression of tumor specific mutations. Sequencing data will be used to 
describe mutational load and impact of clinical covariates on the frequency of mutations. 
 
 
 
 
CCI

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1.5. Summary of the overall benefits and risks 
 
Expected benefits 
TG4050 is an individualized mutanome-directed active immunotherapy designed to trigger a 
specific immune response against patient tumor specific antigens. It is expected that this 
specific response will induce a cytotoxic activity of T cells towards tumor cells potentially 
leading to an improved disease outcome. 
 
Potential risks 
Based on the clinical experience collected for several MVA vector-based immunotherapy 
products investigated by Transgene, the following related adverse events were the most 
common events in clinical trials: 
• Injection site reactions of grade 1 and 2 based on the NCI CTCAE version 5 including 
erythema, inflammation, pain, hemorrhage, pruritus, induration, bruising  
• Lymphadenopathy  
• Headache 
• Pyrexia 
• Fatigue 
• Nausea and vomiting 
• Influenza like illness 
CCI

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Measures taken to mitigate the risks 
The risks-benefits relationship has been carefully considered in the planning of the study. Based 
on the clinical data available to date on other MVA vector-based immunotherapy products, the 
conduct of this study is considered justifiable using the dose and dosage regimen of TG4050 
specified in the study protocol. An Independent Data Monitoring Committee (IDMC) is planned 
for the ongoing assessment of the risk-benefit ratio. The trial shall be discontinued in the event 
of any new finding that indicates a deterioration of the risk-benefit ratio and would render 
continuation of the trial unjustifiable.  
This clinical trial will be conducted in compliance with the clinical study protocol, GCP (ICH 
E6 R2) and the applicable national regulatory requirements. 
 
2. OBJECTIVES 
2.1. Primary Objective 
To evaluate the safety and tolerability of multiple subcutaneous (SC) injections of a neoantigen-
directed active immunotherapy in ovarian, fallopian or peritoneal high-grade serous carcinoma 
(HGSC) patients with an asymptomatic relapse. 
2.2. Secondary objectives 
To evaluate: 
• Failure to provide TG4050 
• Failure to treat with TG4050 
• CA-125 doubling time and half-life as appropriate, time to normalization and response 
according to GCIG criteria 
• Time to measurable relapse in Cohort A and Time to progression in Cohort B per RECIST 
1.1  
• Tumor response by using RECIST 1.1 
2.3. Translational research 
The following exploratory endpoints will be also investigated: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI

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3. STUDY DESIGN 
3.1. Overall study design and plan description 
This is a multicenter, open-label, single arm phase I study evaluating TG4050, an individualized 
active immunotherapy which refers to a mutanome-directed immunotherapy based on a 
Modified Vaccinia virus Ankara (MVA) vaccine specifically designed to target patient-specific 
immunogenic mutations.  
 
The vaccine will be administered at the time of asymptomatic relapse in patients with ovarian, 
fallopian or peritoneal HGSC as a single agent during the treatment period. Patients will receive 
TG4050 at 1x108 PFU by subcutaneous (SC) injections weekly for the first 6 weeks and then 
every 3 weeks up to a total of 20 injections unless disease progression justifying initiation of 
further treatment, unacceptable toxicity including occurrence of a dose-limiting toxicity, or 
patient withdrawal for any reason, whichever occurs first. 
A safety run-in phase will be conducted in the first 3 treated patients from Cohort A or B who 
will be observed during the 6 weeks after the first administration of TG4050. 
During this phase, each patient will be monitored for 4 weeks after the first injection of TG4050 
before the next patient can be enrolled. 
Enrolment of the next patient will be allowed if none of the 3 patients has experienced during 
the 6 weeks run-in phase: 
- 
any grade ≥3 toxicity that is at least possibly related to TG4050, with the following 
exception: pre-existing grade 2 fatigue that would worsen up to grade 3 
- 
any death. 
 
The occurrence of any of those events will trigger study hold. An evaluation of the cause of 
toxicity will be performed and corrective measures if appropriate, will be proposed before 
recruitment in the study can be reinitiated. 
 
The study will consist of 2 parts for each patient: 
 
• A screening period which will start at least 6 months after completion of standard first-
line treatment including a platinum-based chemotherapy. Only patients with histological 
confirmation of serous carcinoma of the ovary, fallopian tube or peritoneum and having 
high risk cancer defined as high grade and stage IIIC or stage IV disease who achieved 
a complete response after chemotherapy defined as non-evidence of disease on the last 
CT-scan and normal CA-125, and from whom tumor tissue is available for tumor 
neoantigen identification can be included in the screening period. 
For those patients, tumor tissue which have been banked at the time of abdominal 
surgery (or at the time of diagnosis if the patient received neoadjuvant chemotherapy) 
and blood samples will be tested for TSAs identification. TSAs will be used to 
manufacture 
an 
individualized 
TG4050 
mutanome-directed 
immunotherapy. 
Manufacturing will take approximately 12 weeks for the vaccine to be prepared in 
accordance with GMP procedures. 
During the screening period, patients will be regularly followed per standard medical 
practice and with serum CA-125 measurements performed in an accredited central 
laboratory at least every 90 to 120 days and imaging in the event of CA-125 increase 
and/or clinical symptoms. If the patient did not relapse after 2 years of follow-up, this 

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follow-up may be performed at least every 6 months (+1 month) according to 
Investigator’s standard practice. Circulating tumor DNA will be followed in peripheral 
samples from study entry and measured in a central laboratory. If a suspicious but 
indeterminate nodule is identified at study entry, repeat imaging should be obtained 3 
months after (+/- 2 weeks) to determinate whether the nodule is malignant. 
Alternatively, a biopsy may be obtained. 
Patients who have developed an asymptomatic relapse according to the below 
definitions are eligible for the treatment period provided they meet the other treatment 
period eligibility criteria. 
 
• A treatment period which will start  
o Cohort A: when patients develop an asymptomatic relapse defined on the basis of 
progressive serial elevations of serum CA-125 (GCIG criteria) or low volume 
radiological disease with CA-125 > Upper Limit of Normal (ULN). Low volume 
radiological disease is defined as radiologically visible disease excluding intra-
hepatic or splenic metastases, ascites or pleural effusion thought to require 
drainage. 
o Cohort B: when patients develop an asymptomatic relapse with measurable 
disease, excluding intra-hepatic or splenic metastases, ascites or pleural effusion 
thought to require drainage, whatever serum CA-125 level and for whom further 
treatment is not planned within 2 months. Longest diameter on CT-scan must not 
exceed 2 cm for non-nodal lesions and 2.5 cm in short axis for nodal lesions  
 
Patients will stop maintenance therapy if any and will receive TG4050. 
 
All treated patients will be followed for: 
• Safety assessments performed on a weekly basis for the first 6 weeks and every 3 weeks 
thereafter. 
• Serum CA-125 levels assessed in an accredited central laboratory within 7 days prior to 
treatment initiation and then every 3 weeks and imaging performed within 21 days prior 
to treatment initiation, at Day 43 and then every 9 weeks. 
• Immune responses evaluated in the blood at baseline and on Days 8, 22, 43, 64 ,85 and 
211; in the tumor at the time of RECIST defined disease progression 
 
A schematic illustration of the trial design is shown below. 
 

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Figure 1: Overall study design 
 
3.2. Number of centers and patients 
In the screening period, an approximate number of 60 patients will be included.  
In the treatment period: 
• Cohort A: at least 13 patients will be enrolled to allow sufficient number of patients 
evaluable for safety, efficacy and immunological analyses. 
• Cohort B: number of patients included at the time of full accrual in Cohort A with a 
maximum of 10 patients. 
The study will be a multicenter one with 3 centers from Mayo Clinic in the US and 3 centers in 
France.  
3.3. Discussion of Study Design  
The first-in-man study of TG4050 is designed as a phase I trial to evaluate primarily the safety 
of TG4050 administered alone in stage IIIC or stage IV HGSC patients with an asymptomatic 
relapse. This clinical setting will also allow the evaluation of serum CA-125 doubling time and 
half-life as appropriate, time to normalization, response according to GCIG criteria and immune 
response to TG4050. 
 
The screening period will run from at least 6 months after completion of first-line platinum-
based chemotherapy to the documentation of an asymptomatic relapse. Patients who achieved 
a complete response as demonstrated by non-evidence of disease on the last CT-scan and 
normal CA-125 can be enrolled. Archived tumor tissue collected at the time of abdominal 
surgery and/or at diagnosis will be used for TSAs identification and subsequent individualized 
TG4050 MVA construct manufacturing. If the patient has received neoadjuvant chemotherapy, 
the tumor tissue must be obtained from a core needle biopsy (18G minimum) performed at 
diagnosis. 
 
The treatment period will run from the documentation of asymptomatic relapse until a total of 
20 injections of TG4050 unless disease progression justifying initiation of further treatment, 
unacceptable toxicity including occurrence of a dose-limiting toxicity or patient withdrawal 
for any reason whichever occurs first. 
 
A safety run-in phase will be conducted in the first 3 treated patients from Cohort A or B who 
will be observed during the 6 weeks after TG4050 first dose. For patients presenting with a 
biochemical relapse detected on the basis of raised serum CA-125 concentration alone, no 
survival benefit has been demonstrated from early chemotherapy treatment compared to 
delayed treatment on the basis of clinical relapse (Rustin G.J. et al., 2010). The lead time 
between CA-125 increase and clinical recurrence was shown to be 4.8 months on average which 
will allow to investigate the tolerance of TG4050. This time period will allow to capture 
immune response to TG4050 and its possible impact on CA-125 doubling time and half-life as 
appropriate, time to normalization and response. In current practice, second-line treatment is 
rarely initiated when relapse is asymptomatic, even in the presence of small measurable lesions, 
and the patient is usually followed with a CT-scan performed 2 months later. National 
Comprehensive Cancer Network guidelines endorse delaying treatment until clinical relapse. 

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This patient population may benefit from study treatment and will be evaluated separately in 
Cohort B. 
3.4. Dose and schedule selection 
Dose and schedule for TG4050 administration have been selected on the basis on the broad 
clinical experience gathered on TG4010, an MVA carrying coding sequences for the human 
MUC1 antigen and human interleukin 2 also developed by Transgene. As of end 2018 a total 
of 354 cancer patients, mostly non-small cell lung cancer (NSCLC) patients, received SC 
injections of TG4010 at a dose of 1x108 PFU weekly for 6 weeks followed by every 3 weeks 
administrations. 
 
• Rationale for the route of administration 
 
In pre-clinical experiments, SC and IM administrations of research grade TG4010 resulted in 
similar anti-tumoral activity as measured by survival in the RMA-MUC1 prophylactic mouse 
model. This finding was repeated with the other Transgene MVA-based gene therapy products. 
The SC route has been chosen from phase II studies of TG4010 and other MVA-based products 
as it appears a more effective route of administration to initiate an immune reaction which is 
the expected mechanism of action for Transgene MVA-based products. It has been 
demonstrated as a safe and immunogenic route in the clinic with MVA-based products. 
 
• Rationale for the dose and regimen: 
 
In TG4010 development, phase II clinical trials were conducted testing different doses and 
schedules of administration of the study drug. 
The dose of 1x108 PFU was selected based on its good tolerance and immunogenicity. 
With its design targeting patient specific neoantigens, TG4050 products should target more 
immunogenic antigens that the ones targeted by MVA-based products already tested in clinic 
by Transgene. It is envisaged that a critical dose threshold needs to be reached to achieve an 
immunogenic response disregarding the nature and immunogenicity of the patient specific 
antigens carried by the MVA vector. This was consolidated by a pre-clinical experiment in 
HLA-A2 mice who received different doses of MVA constructs representative of TG4050 and 
showed response with no dose-response effect. 
Sticking with a dose of 1x108 PFU which allowed immunogenic response with an MVA-based 
product carrying a weak antigen sequence (i.e.: MUC1 antigen for TG4010) should then be 
relevant for TG4050. The high specificity of TG4050 antigens to the human tumor should 
prevent from autoimmune reaction. 
In prostate cancer patients the change in PSA doubling time from before treatment to during 
treatment was statistically significant in patients who received TG4010 weekly for 6 weeks then 
every 3 weeks while this change was not significant in those who received TG4010 every 3 
weeks. Therefore, this treatment regimen was used in all subsequent studies. 
 
• Rationale for repeated administrations scheme: 
 
Therapeutic vaccines do not directly target the tumor but they rather aim at activating and 
amplifying immune reactions against the tumor. Immune responses often take time to develop 
and can potentially be enhanced by continued booster vaccinations. Then a repeated schedule 
of administration was selected for TG4010 as well as the other Transgene MVA-based products 
and is also applied to TG4050 in the clinic. This repeated dose study regimen was shown to be 

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well tolerated, grade 1 or 2 injection site reactions being the most frequent Adverse Events 
(AEs). Importantly this regimen of TG4010 in combination with standard chemotherapy was 
shown to improve patient outcome in a randomized placebo-controlled, double-blind phase 2 
study comparing the combination with chemotherapy and placebo in 222 first-line NSCLC 
patients (Quoix E. et al., 2016). Consistent with repeated injections of TG4010, development 
of CD8+ T cell response to MVA-specific epitopes were observed at different timepoints and 
more frequently in the TG4010 arm in comparison to the placebo arm in this phase 2 clinical 
trial (Tosch C. et al., 2017). Interest of repeated administrations was also evidenced with MVA-
based products not developed by Transgene. For instance, CD4+ and CD8+ T-cell responses to 
MVA or Dryvax were reported in subjects vaccinated with TBC-MVA and responses were 
augmented after three doses of MVA compared to one dose (Parrino J. et al., 2007). 
From an immunologic perspective, there is a theoretical possibility of T cell cross-reactivity 
with repeated administrations of TG4050. This potential risk was previously monitored in 
TG4010 clinical trials assessing repeated administrations of 1x108 PFU through auto-immunity 
parameters assessment (e.g. anti-DNA antibodies, anti-nuclear antibodies, thyroid stimulating 
hormone, anti-thyroperoxidase antibodies). While some of these antibodies increased slightly 
during study compared to pre-treatment level, it was never considered clinically significant by 
the investigators. There was also no clinical evidence of auto-immunity to glandular mucins 
reported (Sjogren’s syndrome). No further autoimmunity clinical issue is expected with 
TG4050 as it targets mutations of patient specific tumor antigen and it has a different 
mechanism of action from checkpoint blockade. Overall the good tolerance and the efficacy of 
the proposed TG4050 regimen have been established for an MVA-based product developed by 
Transgene. 
 
TG4050 will be administered at 1x108 PFU by subcutaneous (SC) injections weekly for the first 
6 weeks and then every 3 weeks up to a total of 20 injections unless disease progression 
justifying initiation of further treatment, unacceptable toxicity including occurrence of a dose-
limiting toxicity, or patient withdrawal for any reason, whichever occurs first. 
 
4. STUDY POPULATION 
4.1. Inclusion criteria 
Screening period  
1. Signed written informed consent in accordance to ICH-GCP and national/local 
regulation before any protocol-related procedures that are not part of normal patient 
care. 
2. Female patients ≥ 18 years of age 
3. Histologically confirmed high grade, stage IIIC or stage IV (FIGO staging) serous 
ovarian, fallopian or primary peritoneal carcinoma with abnormal CA-125 at diagnosis. 
4. Patients who have undergone primary debulking surgery or interval debulking surgery 
and completed a total of at least 5 cycles of taxane-platinum combination. Note: 
patients may have received concurrent or maintenance bevacizumab or a PARP 
inhibitor 
5. Patients must have achieved a complete response to therapy, as demonstrated by no 
residual disease on most recent CT scan and normal CA-125. 
6. Patient who remains disease free at least 6 months from last prior dose of cytotoxic 
chemotherapy (maintenance therapy with bevacizumab or a PARP inhibitor is allowed).  

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7. Available tumor tissue, banked from previous abdominal debulking surgery and/or from 
a core needle biopsy performed at diagnosis if the patient received neoadjuvant 
chemotherapy, and peripheral samples to be submitted to complete exome and 
transcriptome sequencing. 
 
Treatment period: 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at 
treatment period initiation. 
9. Patients who have developed an asymptomatic relapse as defined by:  
• Cohort A: CA-125 ≥ 2 times Upper Limit of Normal (ULN) on 2 occasions at 
least 1 week apart (GCIG criteria) or low volume radiological disease and CA-
125 > ULN. Low volume radiological disease is defined as radiologically visible 
disease excluding intra-hepatic or intra-splenic metastases, ascites or pleural 
effusion thought to require drainage 
• Cohort B: patient asymptomatic with measurable disease excluding intra-
hepatic or splenic metastases, ascites or pleural effusion thought to require 
drainage, whatever serum CA-125 level and for whom further treatment is not 
planned within 2 months. Longest diameter of measurable lesion on CT-scan 
must not exceed 2 cm for non-nodal lesions and 2.5 cm in short axis for nodal 
lesions 
10. Adequate hematological, hepatic and renal functions: 
• Hemoglobin ≥ 9.0 g/dL 
• Neutrophils count ≥ 1.5 x 109/L 
• Lymphocytes count ≥ 0.9 x 109/L 
• Platelets count ≥ 100 x 109/L 
• Total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert’s syndrome) 
• Aspartate aminotransferase (AST) ≤ 2.5 x ULN 
• Calculated creatinine clearance ≥ 45 mL/min using the Cockcroft-Gault 
formula or ≥ 45 mL/min/1.73m² using other methods 
Note: for Cockroft-Gault formula: 
Creatinine clearance for females (mL/min) = 
(140 – age)(weight in kg)(0.85) 
 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 
Creatinine clearance for females (mL/min) = 
(140 – age)(weight in kg)(1.04) 
 
 
 
 
 
 
 
(serum creatinine in µmol/L) 
 
11. Patients who received standard maintenance therapy will stop before initiation of 
TG4050 administration. A free interval of at least 30 days will be respected before first 
dosing of TG4050 except for PARP inhibitors (at least 14 days). 

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4.2. Exclusion criteria 
Screening period 
1. Patient having received any cancer immunotherapy including cancer vaccines, any 
antibody/drug targeting T cell co-regulatory proteins such as anti-PD1, anti-PDL1 or 
anti-CTLA-4 
2. Patients with other active malignancy ≤ 3 years prior to registration except non-
melanoma skin cancer, stage 0 in situ carcinoma and recent early stage papillary thyroid 
cancer. If there is an history of prior malignancy, patients must not be receiving other 
specific treatment for their cancer. 
3. Patient post-organ transplantation, including allogeneic stem cell or bone marrow 
transplantation. History of blood transfusion within 3 weeks prior to study entry visit. 
4. Known history of positive testing for Human Immunodeficiency Virus (HIV) or known 
AIDS (Acquired Immune Deficiency Syndrome). 
5. Any known allergy or reaction to eggs or attributed to compounds of similar chemical 
or biological composition to therapeutic vaccines/immunotherapeutic products. 
6. Positive serology for Hepatis C Virus (HCV), or positive serum Hepatitis B surface 
antigen (HBsAg) within 3 months prior to or at study entry (tests required). 
Treatment period 
7. Measurable disease associated with the appearance of symptoms justifying initiation of 
further treatment. 
8. Major surgery within 4 weeks prior to treatment start 
9. Treatment with another investigational agent within 30 days prior to TG4050 treatment 
initiation. 
10. Patients 
under 
chronic 
treatment 
with 
systemic 
corticosteroids 
or 
other 
immunosuppressive drugs for a period of at least 4 weeks and whose treatment was not 
stopped 2 weeks prior to TG4050 treatment initiation planned date, with the exception 
of patients with adrenal insufficiency who may continue corticosteroids at physiological 
replacement dose, equivalent to ≤ 10 mg prednisone daily. Steroids with no or minimal 
systemic effect (topical, inhalation) are allowed. 
11. Vaccination for the prevention of infectious diseases with a live vaccine during the four-
week period prior to TG4050 treatment initiation planned date. Furthermore, patients 
should not receive any live vaccine during the period of study treatment administration. 
12. Patient with any underlying medical condition that, in the opinion of the investigator, 
could make the patient inappropriate for entry into this study or interfere significantly 
with the proper assessment of safety or toxicity of the study treatment. 
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
14. History of myocardial infarction ≤ 6 months. 
 

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4.3. Criteria for patient premature withdrawal 
 
Premature withdrawal from the trial 
Patients are free to discontinue the trial at any time without giving reasons.  
A patient must be withdrawn in the event of any of the following: 
• Withdrawal of the patient’s consent 
• Participation in any other trial during the duration of this trial 
 
Withdrawal from study treatment period 
Patients must discontinue the study treatment (i.e., for another reason than disease progression 
or death) if any of the following occurs: 
• Significant clinical deterioration (clinical progression), defined as new symptoms that 
are deemed by the investigator to be clinically significant and due to cancer growth. 
However, every effort should be made to document objective progression even after 
discontinuation of treatment 
• Occurrence of a dose-limiting toxicity i.e any treatment-emergent AE grade ≥3 toxicity 
that is at least possibly related to TG4050, with the following exception: pre-existing 
grade 2 fatigue at baseline that would worsen up to grade 3 
• Physician’s decision that further participation in the study is not in the patient’s best 
interest 
• Patient’s request at any time for any reason 
• Protocol violation 
• Lost to follow up 
• TG4050 expiry date reached 
For any discontinuation, the Investigator will obtain all the required details and document the 
date and the reason for the discontinuation in the eCRF. In any case of treatment discontinuation 
not related to disease progression the patient will be followed per protocol until documentation 
of disease progression. 
If the reason of stopping the treatment is an AE, the specific event will be recorded in the eCRF. 
The Investigator will make thorough efforts to document the outcome. 
As far as possible, no patient should leave the study without having undergone the end of 
treatment visit and the safety follow-up visit. 
 
Replacement policy 
In the safety run-in phase part of the trial (3 first patients), only patients who do not complete 
the DLT observation period (the first 6 weeks of study treatment) for other reasons than a DLT 
or who are not evaluable for safety analysis will be replaced. Evaluable patients’ populations 
are defined in section 9.1.  
If some patients have not progressed within 36 months after vaccine manufacture, patients will 
be withdrawn from study. Patients will not be replaced. 
4.4. Definition of end of study 
The end of study is defined as the date of the last patient last visit. 

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The end of study page in the eCRF will be filled in when patient withdraws the study due to 
any reason or if the patient dies or progresses. The patient will be considered as completer if 
she received the 20 injections or progresses or dies or withdraws due to a DLT before the end 
of treatment.  
In addition, the shelf life of TG4050 is 48 months. Considering the planned duration of 
treatment lasting around 11 months with pre-treatment assessments of around 1 month 
(confirmation of asymptomatic relapse and baseline visit), patients will need to start treatment 
at least 12 months before the expiry date. Otherwise, patients will be withdrawn from the trial 
prior treatment period initiation and their end of study would be defined as the date of study 
withdrawal. 
 
 
5. REGISTRATION PROCEDURES 
 
The study design will require two registration procedures, one for the screening period and the 
other for the treatment period. 
5.1. Screening period 
At least six months after chemotherapy completion, the patient who meets the eligibility criteria 
will sign an informed consent form (ICF) and will be assigned a 15-digit identification number 
which is a combination of the study code (TG4050-01), the 4-digit center number and the 3-
digit patient number. The center number is assigned by Transgene to the investigational site. At 
each site the first patient screened is assigned patient number 001 and subsequent patients are 
assigned consecutive numbers. Once assigned to a patient, the patient number will not be 
reused. 
For patients having archived tumor tissue, eligibility will be verified. If the patient is not 
included for any reason, the reason for non-inclusion and a minimum of other parameters (date 
of ICF signature, demographics and disease characteristics) will be entered in the eCRF. 
5.2. Treatment period 
At the time of asymptomatic relapse, the patient for whom TG4050 is available will start 
treatment period. The patient will keep the same identification number for the treatment period. 
The baseline assessment will last at most 21 days. Tests performed per standard of care (e.g., 
CT-scan) may not need to be repeated if collected within 28 days prior to start of study 
treatment. 
If the patient is not included for any reason, the reason for non-inclusion and a minimum of 
other parameters (results of the baseline assessment) will be entered in the eCRF. 
 
 
6. STUDY VISITS AND PROCEDURES 
 
A flow chart in Appendix II summarizes the evaluations to be performed along with the 
timepoints for each period of the study and the data to be collected in the eCRF. 
6.1. Screening period 
 
Evaluation description 
• Demography 

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- 
Date of birth 
 
• History of HGSC cancer  
- 
Date of diagnosis and abdominal surgery 
- 
Confirmation of the High Grade  
- 
Confirmation of the Stage at diagnosis (IIIC or IV) 
- 
Confirmation of the Histologic type (Serous) 
- 
Primary tumor location 
o BRCA 1 and 2 status and other molecular characteristics if available (e.g: 
other mutations of interest, Human Recombination Deficiency status by 
Genomic Instability Score, Loss of Heterozygosity testing, Telomeric Allelic 
imbalance or Large scale transition or other metrics) 
- 
Prior antineoplastic therapies, including date, setting and type of chemotherapy and 
date of documentation of response 
- 
Maintenance therapy if any 
 
• Relevant medical history 
- 
Relevant medical history with established diagnosis present or recovered at ICF 
signature 
 
• Clinical evaluation 
- 
Physical examination of the major organ systems, including vital signs (body 
temperature, pulse rate and blood pressure) and weight (height to be collected at 
screening only) 
 
• Concomitant medications and significant non-drug therapies 
 
• Reporting of Serious Adverse reactions (SARs) caused by a protocol required 
procedure 
 
• Blood sampling 
- 
HCV serology; detection of Hbs antigen if not performed within 3 months prior to 
study entry. 
- 
Blood sampling needed for HLA typing and generation of reference exome 
 
• Tumor tissue availability 
- 
Tumor tissue obtained at the time of abdominal surgery and/or at the time of 
diagnosis if the patient received neoadjuvant chemotherapy (18G core needle 
biopsy) will be used for TSAs identification and translational research (see protocol 
section 8.2.6). 
 
• CA-125 assessed in an accredited central laboratory 
- 
Serum concentration will be assessed as per standard medical practice and at least 
every 90 to 120 days from study entry. If the patient did not relapse after 2 years of 
follow-up, this follow-up may be performed at least every 6 months (+1 month)  
according to Investigator’s standard practice. 
 

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• CtDNA assessed in a central laboratory: every 90 to 120 days from study entry. If 
the patient did not relapse after 2 years of follow-up, this follow-up may be performed 
at least every 6 months (+1 month) according to Investigator’s standard practice. 
 
• Tumor imaging 
- 
Regular visits will be scheduled as per standard medical practice. CA-125 increase 
above ULN or occurrence of symptoms or clinical signs will be an indication for 
imaging. 
 
Patient eligibility is to be established by the investigator by confirming that all 
inclusion/exclusion criteria are met. Deviation from any eligibility criteria excludes a patient 
from participating into the study. 
 
Study entry visit 
Once the informed consent is signed, the following will be performed: 
• Collection of demographics data 
• Recording of history of HGSC and relevant medical history 
• Complete response (non-evidence of disease) checked on imaging performed within 28 
days prior to or at study entry visit. If a suspicious but indeterminate nodule is identified 
at study entry, repeat imaging should be obtained 3 months after (+/- 2 weeks) to 
determinate whether the nodule is malignant. Alternatively, a biopsy may be obtained   
• Physical examination of major organ systems, including vital signs, weight and height 
• Recording of concomitant medications and significant non-drug therapies 
• HCV serology; detection of HBs antigen if not performed within 3 months prior to study 
entry 
• CA-125 concentration 
• ctDNA measurement 
• Verification of eligibility criteria 
• Request for TG4050 manufacturing 
- 
Tumor tissue sample banked to be sent to sequencing/central laboratory 
- 
Blood sample collected to be sent to sequencing/central laboratory 
 
Follow-up visits in patients with Complete Response 
Follow-up visits will be performed at least every 90 to 120 days in accordance with standard 
medical practice and include: 
• Physical examination, including vital signs and weight (according to local practice, 
physical examination and vital signs can be done every 6 months beyond 2 years after 
surgery) 
• Concomitant medications and significant non-drug therapies 
• CA-125 concentration  
• ctDNA measurement 
• Imaging per standard practice and if symptoms or clinical signs occur or if CA-125 
increases. 
If the patient did not relapse after 2 years, these follow-up visits may be performed at least every 
6 months (+1 month) according to Investigator’s standard practice. 

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Asymptomatic relapse study visit 
Each time CA-125 value is above the ULN during the follow-up post-chemotherapy, an 
asymptomatic relapse assessment will be conducted at least one week later per regular medical 
practices with: 
• Physical examination, including vital signs and weight 
• Concomitant medications and significant non-drug therapies 
• CA-125 concentration (for increase confirmation) 
• Imaging  
 
Based on CA-125 serum concentration and imaging monitoring in asymptomatic relapse study 
visit, it will be considered that a patient has developed an asymptomatic relapse when: 
Cohort A: 
- 
the patient has CA-125 ≥ 2 times ULN on 2 occasions at least 1 week apart  
or 
- 
the patient has low volume radiological disease and CA-125 > ULN. Low volume 
radiological disease is defined as radiologically visible disease excluding intra-hepatic 
or intra-splenic metastases, ascites or pleural effusion thought to require drainage. 
Cohort B: 
- 
the patient is asymptomatic but develops measurable disease excluding intra-hepatic or 
intra-splenic metastases, ascites or pleural effusion thought to require drainage, whatever 
serum CA-125 level and for whom further treatment is not planned within 2 months. 
Longest diameter on CT-scan must not exceed 2 cm for non-nodal lesions and 2.5 cm in 
short axis for nodal lesions. 
When a patient has developed an asymptomatic relapse, a request for clinical supply of 
TG4050 individualized product will be sent by the clinical site to Transgene. 
6.2. Treatment period 
Treatment with TG4050 will be initiated in eligible patients for whom the individualized MVA 
construct is available. 
Patients not eligible or for whom the individualized TG4050 product is unavailable will 
continue to benefit from routine medical monitoring and will receive SOC in case of recurrence 
as per normal practice. 
 
Evaluation description 
The following parameters will be measured during this period: 
• Inclusion/exclusion criteria 
Patient eligibility is to be established by the investigator by confirming that all the treatment 
period inclusion / exclusion criteria are met. Deviation from any eligibility criterion 
excludes a patient from registration into the treatment period. 
 
• Current medical conditions 
- 
Syndrome/pathology with established diagnosis starting during the screening period 
either recovered or ongoing 
- 
“Signs and symptoms” symptoms with no associated syndrome (e.g., diarrhea) see 
section 8.2 

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• Clinical evaluation 
- 
Physical examination of major organ systems, including vital signs (body 
temperature, pulse rate and blood pressure) and weight 
- 
PS on ECOG scale (see APPENDIX I) 
 
• Concomitant medications and significant non-drug therapies 
 
• Electrocardiogram (12 leads) 
- 
At baseline, every 3 weeks for the first 6 weeks and then every 6 weeks up to Day 
169, thereafter every 12 weeks, and at the end of treatment visit 
 
• Safety assessments 
- 
AEs/SAEs collection see section 8.2 
- 
Follow-up of all ongoing AEs 
 
• Laboratory assessments 
- 
CBC including RBC, Hb, WBC and differential, platelets 
- 
Biochemistry including AST, ALT, alkaline phosphatases, total bilirubin, glucose, 
electrolytes (sodium, potassium, magnesium and bicarbonates), creatinine and 
creatinine clearance 
 
• Blood sampling and cytapheresis for translational research; if the post-baseline 
cytapheresis procedure is not clinically feasible, it can be replaced by a 150 ml blood 
draw. 
 
CA-125 evaluation in an accredited central laboratory, serum concentration will be 
assessed every 3 weeks 
 
• Tumor imaging 
- 
A CT-Scan of the pelvis and abdomen (or MRI) and X-ray or preferably CT-scan of 
the chest will be performed within 21 days prior to treatment initiation, on Day 43 
and then every 9 weeks with a time window of +/- 7 days until disease progression 
justifying initiation of further treatment  
 
 
Baseline visit 
The following procedures will be performed within 21 days prior to treatment start: 
• Inclusion/exclusion check 
• Physical examination, including vital signs and weight 
• PS on ECOG scale 
• Current medical conditions and signs/symptoms see section 8.2 
• Concomitant medications 
• Electrocardiogram 
• Tumor assessment by imaging procedures if the previous imaging has been performed 
more than 4 weeks before treatment start 

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The following procedures must be performed within 7 days prior to the first dose: 
• Inclusion/exclusion check 
• Blood analyses including: 
- 
CBC including RBC, Hb, WBC and differential, platelets 
- 
Biochemistry tests 
- 
CA-125 concentration 
- 
Blood sample and cytapheresis for translational research 
 
Study visits during the treatment period 
The time windows allowed for the visits are: 
• +/- 1 day for the first 6 weeks 
• +/- 7 days beyond the first 6 weeks 
During the first 6 weeks 
On a weekly basis, the following investigations must be performed: 
• Physical examination, including vital signs and weight 
• PS on ECOG scale 
• Adverse events reporting 
• Concomitant medications 
• CBC including RBC, Hb, WBC and differential, platelets 
• Biochemistry tests 
On an every three-weeks basis, the following investigations must be performed: 
• CA-125 concentration 
• Electrocardiogram 
For translational research: 
• 
 
Imaging at Day 43 
Beyond 6 weeks 
On an every three-week basis, the following investigations must be performed: 
• Physical examination, including vital signs and weight 
• PS on ECOG scale 
• Adverse events reporting 
• Concomitant medications 
• CA-125 concentration 
CBC including RBC, Hb, WBC and differential, platelets & Biochemistry every 3 weeks up to 
Month 6 (Day 190), thereafter every 12 weeks. 
ECG every 6 weeks up to Day 169, thereafter every 12 weeks. 
From Day 43, tumor assessments by imaging procedures must be performed every 9 weeks. 
For translational research: 
• 
 
CCI
CCI

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• Cytapheresis on Day 64; if not clinically feasible, the cytapheresis procedure can be 
replaced by a 150 ml blood draw. 
 
End of treatment visit  
An end of treatment visit will be performed within 7 days after study treatment is completed or 
stopped for whatever reason (disease progression, unacceptable toxicity including dose-limiting 
toxicity or, patient withdrawal due to any reason). The end of treatment visit and the last visit 
planned for treatment administration can be performed on the same day provided that all 
evaluations and blood samples required at both visits are performed (except if repeated exams). 
 
The following evaluations will be conducted: 
• Physical examination, including vital signs and weight 
• PS on ECOG scale 
• Adverse events reporting  
• Concomitant medications 
• CBC including RBC, Hb, WBC and differential, platelets 
• Biochemistry tests 
• Electrocardiogram 
• Reporting of subsequent cancer therapy if applicable 
• For translational research, a blood sample and tumor sample will be collected at the time 
of documented disease progression when clinically feasible. 
• Cytapheresis: in case patient is withdrawn prior to Day 64, a cytapheresis is to be performed 
at the end of treatment visit. If not clinically feasible, it can be replaced by a 150 ml blood 
draw. 
 
Follow-up for secondary activity endpoints  
In case the study treatment discontinuation is not due to progressive disease or death, the patient 
will be followed for secondary endpoints (CA-125 evaluation, Time to measurable relapse or 
progression justifying initiation of further treatment) or until the date of last contact if the patient 
is lost to follow-up or withdraws consent. A CT-scan or MRI as well as CA-125 measurement 
must be obtained every 9 weeks until disease progression and recorded in the eCRF. All 
subsequent antineoplastic therapies (if applicable) must be recorded in the eCRF with start and 
end dates. 
 
Safety Follow-up visit  
A safety follow-up visit will be performed at least 30 days (+14 days allowed) after the last 
dose of study treatment. 
The following evaluations will be conducted and recorded in eCRF: 
• Physical examination, including vital signs and weight 
• PS on ECOG scale 
• Adverse events reporting 
• Concomitant medications 
• Reporting of subsequent cancer therapy if applicable 

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For patients who refuse to return for a visit, they will be contacted by phone to obtain this 
information if possible. 
 
 
7. TREATMENT PLAN FOR TREATMENT PERIOD 
7.1. Investigational Medicinal Product (IMP) characteristics 
In this clinical trial, the Investigational Medicinal Product (IMP) is TG4050. 
 
TG4050 is a suspension of a recombinant MVA strain, a significantly attenuated strain of 
Vaccinia virus, containing DNA sequences coding for several patient tumor specific antigens 
(TSAs). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TG4050 will be supplied along with a Technical Sheet detailing its characteristics. 
 
Manufacturing 
For patients who meet screening period eligibility criteria, tumor tissue which have been banked 
at the time of surgery and/or at the time of diagnosis if the patient received neoadjuvant 
chemotherapy (18G core needle biopsy), and blood samples will be tested for TSAs 
identification. TSAs will be used to manufacture an individualized TG4050 mutanome-directed 
immunotherapy. Manufacturing will take approximately 12 weeks for the vaccine to be 
prepared in accordance with GMP procedures. 
 
In case of TG4050 individualized construct unavailability in due time or no injection of TG4050 
manufactured product for any reason, the reason will be documented as a Failure to provide or 
a Failure to treat and the patient will be withdrawn from the study. They will continue to benefit 
from routine medical monitoring and will receive SOC in case of recurrence as per normal 
practice. 
 
Due to rapid progression of the disease, another round of manufacturing attempt could not be 
considered in case of Failure to provide or Failure to treat. 
 
Packaging and labeling 
TG4050 is supplied as a frozen suspension filled in individual 2-mL glass vials (Type I glass). 
Each vial is intended for single use (i.e., 1 injection to 1 patient). The recoverable volume of 
TG4050 in each vial is 0.5 mL with an infectious titer of 1x108 PFU. TG4050 is a colorless to 
whitish clear or slightly turbid liquid, with possible presence of product particles or filaments. 
CCI

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The primary label on the vial as well as the secondary label on the secondary packaging are in 
the language of countries where the study is to be performed. Labels are compliant with local 
regulatory requirements. 
 
Packaging for shipment of TG4050 is compliant with the IATA (International Air Transport 
Association) and ADR (International Carriage of Dangerous Goods by Road) regulations for 
air and road transport of infectious substances (UN 373 regulations). TG4050 is shipped in 
proper transport conditions with the official transport designation “Biological Substance, 
Category B” by a carrier specialized in Genetically Modified Organisms (GMO) transportation. 
 
Conditions of storage and use 
TG4050 must be stored at -20°C +/- 5°C (between -15°C and -25°C), which is equivalent to -
4°F +/- 9°F (between +5°F and -13°F), in an alarmed and monitored freezer in a secure place 
with restricted access until use under the supervision of the study Pharmacist / Investigator (or 
his/her delegate). The vials will be dispensed only with the written authorization of the 
Investigator to staff that have been specifically designated and trained for this study. 
TG4050 is a Genetically Modified Organism (GMO). As such, and whenever relevant, it must 
be handled according to national regulatory requirements. The Investigator’s Brochure, as well 
as the Technical Sheet provided by Transgene provide instructions for TG4050 handling 
(biosafety requirements, preparation, administration, destruction) and incident management. 
During all TG4050 handlings, lab coat, goggles, gloves and mask must be worn. All transport 
of TG4050 (vial or syringe containing the dose to be injected) must be done using a leakproof 
container/bag. 
 
Preparation and administration procedure 
TG4050 doses will be prepared and handled according to the instructions provided in a 
Preparation Procedure provided by Transgene.  
 
TG4050 must be prepared under aseptic conditions in compliance with requirements for every 
human injectable preparation. Aseptic conditions mean the standard hospital conditions for 
injectable preparations that ensure the sterility of the TG4050 solutions.  
 
Each TG4050 dose will be administered by a single SC injection. Four injection sites will be 
used (left and right arm, left and right thigh) according to a rotation schedule. It is preferable 
that the first injection is administered in either the right or left thigh. The second injection is to 
be given in the opposite side arm, the third in the same side thigh, and the fourth in the opposite 
side arm. For example, if the left thigh is the site of the first vaccination, the second vaccination 
would be in the right arm, the third in the right thigh, and the fourth in the left arm. This pattern 
is recommended and will be repeated for subsequent injections. 
 
 
Inj 1 in Left thigh 
----> Inj. 2 in Right Arm 
  
 
 
 
Inj. 5  
 
    Inj. 6 
 
 

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Inj. 4 in Left Arm 
--- 
Inj. 3 in Right Thigh 
  
 
 
 
Inj. 8  
 
     Inj. 7 
If the pattern cannot be followed exactly, it is more important to alternate between the arms and 
thighs than side to side. 
 
In case of incident while handling TG4050, the actions recommended are described in the 
Technical Sheet. 
 
Any incident must be documented by a written report to be sent as soon as knowledge of the 
event to Transgene Medical Department or its designee: 
 
Emergency 24-hour telephone number (international):  (33) (0)3 68 33 28 80 
 
Disposal and destruction or return 
During the course of the study based on Transgene’s request and at termination of the study all 
unused TG4050 will be destroyed locally or returned to Transgene. 
 
For local destruction, the Investigator/Pharmacist or delegated person will ensure that 
destruction is performed according to written instructions for disposal of TG4050 and waste 
generated during the TG4050 preparation and administration (e.g. injected and non-injected 
syringes, needles, gloves, etc.) available in the TG4050 Investigator’s Brochure and the 
Technical Sheet, and will not expose humans to any risks from TG4050. A certificate of 
destruction will be completed and provided to Transgene (copy retained by the site). 
 
Alternatively, unused vials of TG4050 may be returned to Transgene with the appropriate 
documentation. Transgene will coordinate the return of unused vials of TG4050. A certificate 
of return will be completed and provided to Transgene (copy retained by the site). 
All along the study, the monitor will verify that all used TG4050 vials and waste linked to 
TG4050 handling are disposed locally, all unused/expired vials are returned or destroyed 
locally, and no product remains on site upon completion or termination of the study. 
Accurate records of TG4050 received at, dispensed from, returned to and disposal of by the 
study site should be recorded appropriately on the drug log. 
 
Supplier 
TG4050 will be supplied by Transgene for this study at no cost to the study participant. 
7.2. Treatment duration 
Study treatment will be administered up to a total of 20 injections unless disease progression 
justifying initiation of further treatment, unacceptable toxicity including occurrence of a dose-
limiting toxicity, or patient withdrawal due to any reason, whichever occurs first. 

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7.3. Treatment modification 
No dose reduction is allowed. 
If a grade 1 occurs, TG4050 should be administered as planned. In case a grade ≥ 2 treatment-
emergent AE occurs, that is at least possibly related to TG4050, the administration of TG4050 
will be delayed until resolution to grade ≤1 with the following exceptions: fatigue and injection 
site reactions which are common vaccine-associated AEs. The decision to restart TG4050 or to 
permanently discontinue study treatment will be discussed between the investigator and 
Transgene. 
7.4. Treatment compliance 
 
Dispensing and accountability 
TG4050 will only be dispensed, according to Investigator’s prescription, to patients who meet 
all eligibility criteria. 
The Investigator / Pharmacist or delegated person will maintain IMP accountability records for 
TG4050, detailing the dates and quantities dispensed for each patient along with IMP packaging 
batch numbers, box and vial numbers. 
IMP accountability records will be verified by the monitor during site monitoring visits. All 
used and unused IMP will be accounted for. All unused IMP will be destroyed locally or 
returned to Transgene, providing destruction or return certificates (see sections 7.1.5 and 7.1.6).  
 
Assessment of compliance 
The compliance for the IMPs will be monitored through the IMP accountability logs and 
information reported on the eCRF pages. 
7.5. Concomitant medications 
 
Prohibited and/or restricted medications during study treatment 
The following medications are prohibited (unless utilized to treat a drug-related adverse event): 
• Immunosuppressive agents 
• Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.5.3) 
• Any 
concurrent 
anti-neoplastic 
therapy 
(ie, 
chemotherapy, 
hormonal 
therapy, 
immunotherapy, radiation therapy, or another standard or investigational agents for 
treatment of ovarian cancer) 
• Any live vaccine for the prevention of infectious disease  
• Any other investigational agent 
 
The following non-drug therapies must not be used during the study (and within 28 days before 
the start of trial treatment): 
• Herbal remedies with immunostimulating properties (e.g., mistletoe extract) or known to 
potentially interfere with major organ function (e.g., hypericin) 
• Major surgery 
 

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If the use of a non-permitted concomitant therapy becomes necessary during the trial, the patient 
should be withdrawn from trial treatment (Transgene may be contacted to discuss whether the 
trial treatment must be discontinued).  
 
Permitted medications/therapies 
• Patients are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). 
• The use of the following drugs will not be restricted during the course of the study: G-CSF, 
erythropoietin, antiemetics and analgesics.  
• The use of systemic corticosteroids during the study is restricted as follows: for short term 
treatment (≤7 days) of allergic reactions, or for replacement for adrenal insufficiency at doses 
equivalent to ≤ 10 mg prednisone daily. 
• Any medications (other than those excluded by the study protocol) that are considered 
necessary for the patients’ welfare and will not interfere with the trial medication may be 
given at investigator’s discretion. 
7.6. Medical care of patients after end of study 
After a patient has completed the trial or has withdrawn early, usual treatment will be 
administered, if required, in accordance with the trial site’s standard of care and generally 
accepted medical practice and depending on the patient’s individual medical needs. 
Upon withdrawal from study treatment, patients may receive whatever care they and their 
physicians agree upon. 
 
 
8. EVALUATION 
8.1. Evaluation of screen failure 
The percentage of patients who cannot be enrolled in the treatment period and the reason that 
prevents patients from being treated will be evaluated.  
The reasons can be: 
• Failure to provide the vaccine (e.g., no mutations identified) or failure to treat (e.g., non-
eligibility of the patients for the treatment period) 
• Lost to follow-up 
8.2. Evaluation during the treatment period 
 
Efficacy evaluation 
CA-125 evaluation 
CA-125 concentration assessed in an accredited central laboratory will be measured every 3 
weeks from the start of study treatment until treatment discontinuation for any reason including 
documented disease progression by RECIST 1.1. For patients who stopped the study treatment 
before documentation of disease progression, CA-125 measurements should then be performed 
every 9 weeks until documented progression.  A CA-125 response is defined as at least a 50 % 

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reduction in CA-125 concentrations from a pretreatment sample according to GCIG criteria. 
The response must be confirmed and maintained for at least 28 days. 
CA-125 doubling time and half-life as appropriate, time to normalization will also be analyzed 
during the study treatment period. 
 
Tumor evaluation 
Tumor response will be evaluated according to RECIST 1.1. Tumor assessment will be 
performed within 21 days prior to treatment start, at Day 43 and then every 9 weeks until disease 
progression justifying further treatment and will require CT-scans of the pelvis and abdomen 
and (X-ray or preferably CT-scan) of the chest. MRI can be used for patients who are allergic 
to radiographic contrast media. Throughout the study, the same assessment technique must be 
used. 
 
Safety evaluation 
Safety assessments will consist of monitoring and reporting of all adverse events (AEs) and 
serious adverse events (SAEs), physical examination findings including vital signs and 
laboratory tests (see Appendix II). 
The safety assessments will be performed according to the schedule of assessments in Appendix 
II-B. 
8.2.2.1. 
Definitions 
Treatment-Emergent Adverse Event (TEAE) 
A treatment-emergent adverse event (TEAE) is defined as a sign or symptom that emerges 
during treatment or within 30 days after the last dose of the study drug, having been absent pre-
treatment or that has worsened relative to the pre-treatment state. 
Adverse Event (AE) 
An Adverse Event is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation patient administered study treatment 
and that does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of study treatment, whether or not considered related 
to the study treatment. 
 
Adverse reaction (AR) 
All noxious and unintended responses to a medicinal product related to any dose or to a study 
specific procedure. 
 
Dose-limiting toxicity (DLT) 
Any of the following treatment-emergent AE occurring during the first 6 weeks after TG4050 
administration: 
- 
any grade ≥3 toxicity that is at least possibly related to TG4050, with the following 
exception: pre-existing grade 2 fatigue at baseline that would worsen up to grade 3 
- 
any death. 
The occurrence of one of those events in the initial 3 treated patients will trigger study hold. 
 

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Beyond the safety run-in phase, a dose-limiting toxicity is defined as any treatment-emergent 
AE grade ≥3 toxicity that is at least possibly related to TG4050, with the following exception: 
pre-existing grade 2 fatigue at baseline that would worsen up to grade 3. 
 
In any case, patients experiencing a dose-limiting toxicity will discontinue study treatment 
permanently. 
 
Serious adverse events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
• results in death 
• is life-threatening (defined as an event in which the patient was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect  
• is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the patient or may require intervention (e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
drug is an SAE.  
Although overdose and cancer are not always serious by regulatory definition, these events 
must be handled as SAEs. (see Section 8.2.4). 
 
NOTE 
The following situations do not need to be reported as SAEs:  
• Elective hospitalization for pre-existing conditions that have not been exacerbated by trial 
treatment. 
• Hospitalization which was planned before the patient consented for study participation and 
where admission did not take longer than anticipated. 
• Hospitalization planned for protocol related treatment or protocol related procedure as per 
institutional standard timelines. 
• Social and/or convenience admission to a hospital. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to 
the procedure is an (S)AE. 
• Situations where an untoward medical occurrence did not occur (palliative care, 
rehabilitation, overdose without occurrence of an adverse event). 
• Hospitalization for anticipated day-to-day fluctuations of pre-existing disease(s) or 
condition(s) present or detected at the start of the study that do not worsen. 

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Suspected Unexpected Serious Adverse Reaction (SUSAR): 
A SUSAR is any unexpected SAE considered as related to the study treatment or to a study 
specific procedure. 
Expected adverse events are those adverse reactions that are listed or characterized in the 
reference document (e.g., IB). 
Unexpected adverse reactions are those not listed in the reference document or not identified. 
This includes adverse events for which the specificity or severity is not consistent with the 
description in the reference document.  
8.2.2.2. 
Time period for collection 
From the date of signature of ICF and up to first TG4050 administration, only serious adverse 
reactions (SARs) caused by a protocol-required procedure will be collected and reported (refer 
to section 8.2.2. and 8.2.3). The only protocol-required procedure concerned is the specific 
blood sample taken during the screening period.  
AEs, SAEs, or procedure related ARs that occur between ICF signature and 3 weeks prior to 
first administration, and that are considered by the investigator as particularly relevant to the 
patient’s condition, will be collected as a current medical history.  
If an event occurs during the period from 21 days before and up to first TG4050 administration, 
it will be recorded either on a “Medical history/current conditions” page for an identified 
syndrome (e.g., pneumonia) or on a “Signs and symptoms” page for symptoms with no 
associated syndrome (e.g., diarrhea).  
 
From the first TG4050 administration and in case of worsening of a sign and symptoms which 
started 21 days before first TG4050 administration, an AE page will be completed using a 
verbatim starting by “worsening of...” 
From the initiation of TG4050 treatment up to the safety follow-up visit (at least 30 days after 
the last administration of study treatment), all AEs and SAEs should be collected and recorded 
on the eCRF. During this period all SAEs should also be reported to Transgene.  
All SARs related to a study specific procedure occurring during the screening period and all 
SAEs occurring during the treatment period will be recorded in Transgene safety database.  
 
SAEs occurring more than 30 days after administration of the last dose of TG4050 and 
evaluated by the investigator as related to TG4050 should be collected and reported to 
Transgene indefinitely even after study closure. These will however not be reported in the eCRF 
after Database lock. 
8.2.2.3. 
Adverse event / Serious adverse event management 
8.2.2.4. 
Data collection 
Reporting in eCRF 
At each visit, all AEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately on the page “Adverse Events” of the eCRF (= AE page). The following 
items must be documented: 

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• nature of the event with self-explanatory and concise medical terminology (if possible 
indicate a diagnosis or syndrome instead of symptoms), 
• date of onset and date of end (i.e. actual dates when the event starts and is resolved rather 
than dates when the Investigator is informed), 
• intensity, 
• evaluation of seriousness, 
• relation to study treatment or to study procedures, 
• action taken regarding the study treatment, 
• action taken regarding the event, 
• outcome. 
 
AE / AR requiring therapy must be treated with recognized standards of medical care to protect 
the health and well-being of the patient. Any treatment given will be reported on the page 
"Concomitant medication" of the eCRF. 
Appropriate resuscitation equipment and medicines must be available to ensure the best 
possible treatment of an emergency situation. 
 
 
Intensity 
The intensity of AE/SAE will be graded according to the NCI-CTCAE (version 5) which will 
be provided to the Investigators. 
Should an event be missing in the CTCAE, the following 5-point scale is to be used: 
• Mild: 
 
Discomfort noticed, but no disruption of normal daily activity 
• Moderate:  
Discomfort sufficient to affect normal daily activity 
• Severe: 
 
Inability to work or perform normal daily activity 
• Life-threatening:  Risk of death at the time of the event 
• Fatal: 
 
The patient died 
 
The correspondence between the two scales is as follows: 
CTCAE 
5-point scale 
1 
Mild 
2 
Moderate 
3 
Severe 
4 
Life-threatening  
5 
Fatal 
 
Any increase or decrease in severity category during the course of an adverse event should be 
reported on the AE pages of the eCRF with corresponding dates. 
 
Causality 
The relationship to IMP of each AE/SAE will be evaluated by the Investigator with 
EudraVigilance Clinical Trial Module” (EVCTM) method using the following levels: 
• No reasonable possibility (i.e. no facts (evidence) or arguments to suggest a causal 
relationship): the temporal relationship of the clinical event to the administration of study 

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treatments makes a causal relationship unlikely; and other drugs, therapeutic interventions 
or underlying conditions provide a sufficient explanation for the observed event. 
•  Reasonable possibility (i.e. facts (evidence) or arguments to suggest a causal relationship): 
the temporal relationship of the clinical event to the administration of the study treatments 
makes a causal relationship possible; and other drugs, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the observed event. A 
clear-cut temporal association with improvement on cessation of the study treatment or 
recurrence upon rechallenge may also be observed. 
 
Outcome 
The outcome is rated as follows: 
• recovered,  
• not recovered, 
• worsening 
• recovering, 
• recovered with sequelae, 
• fatal, 
• unknown. 
 
Note on "fatal": this outcome is to be used only for the event leading to death. The outcome of 
all other events at the time of the death must be reported. The outcome of ongoing ones is 
reported as "not recovered". 
 
Action taken regarding the IMP  
• None: 
 administration continues as planned in the protocol 
• Delayed: 
 administration following the occurrence of the event is delayed 
• Cancelled:  
administration following the occurrence of the event is cancelled 
• Stopped:  
administration is definitively stopped 
• Not applicable: 
administration is already stopped, or study treatment not started yet 
 
Action taken regarding the event 
• New treatment prescribed or change in concomitant medication 
• Hospitalization or prolongation of hospitalization 
• Non-drug therapy implemented  
• None 
• Other (to be specified) 
8.2.2.5. 
Follow-up 
Once an AE is detected, it must be proactively followed until its resolution or 30 days after the 
last study treatment administration. 
However, the AEs listed below must be followed until they are resolved or stable or returned 
to baseline status, which may occur after the safety follow-up visit planned by the protocol: 
• AE evaluated as related to the IMP 
• SAEs 

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• Any other significant AE as recommended by Transgene 
 
Transgene or its representative reserves the right to ask for further information on any AE/SAE 
that may be considered of interest or when the event is not previously documented in the IB 
(new occurrence) is thought to be related to the IMP. 
8.2.2.6. 
Documentation 
All AEs/SAEs will be reported in the source document with at least the nature, the date of onset 
and end, the causality, and the treatment (if applicable). 
Copies of SAE form will be filled in the Investigator Site File along with copies of any 
correspondence with the Independent Ethics Committee (IEC) / Institutional Review Board 
(IRB). The Investigator Site File will also include copies of notification letters and/or faxes 
with forms sent to Health Authorities and Gene Therapy Bodies if appropriate. 
8.2.2.7. 
Notification to investigators 
In case of a grade ≥ 3 AE suspected to be related to TG4050 occurs, Transgene or its 
representative will inform all investigators involved in the study that such an event has been 
reported as soon they became aware. 
 
Serious Adverse Event / Serious Adverse Reaction / Suspected 
Unexpected  Serious Adverse Reaction notification 
Reporting to Transgene 
Any SAE occurring during the screening period (after ICF signature and before TG4050 
treatment initiation) related to a study specific procedure (specific blood sample taken during 
the screening period) MUST be reported to Transgene.  
Any SAE occurring during the treatment period (from TG4050 treatment initiation and up to 
30 days after last study treatment administration) whether or not related to TG4050 MUST be 
reported to Transgene.  
SAEs occurring more than 30 days after administration of the last dose of TG4050 and 
evaluated by the investigator as related to TG4050 MUST be reported to Transgene.  
The Investigator must complete and send (preferably by email otherwise by fax) a "Serious 
Adverse Event Form" to Transgene within 24 HOURS of occurrence or knowledge of the event. 
 
 
 
France 
Pharmacovigilance Physician  
Name 
 
Phone number 
 
Fax number 
 
Email 
  
Emergency 24-hour telephone number 
 
 
 
PPD
PPD
PPD
PPD
PPD

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An Investigator’s designee may complete the SAE form; however, the Investigator must sign 
it. The form can be sent to Transgene with the designee's signature if the Investigator's signature 
cannot be obtained within one working day. The Investigator's signature must be obtained as 
soon as possible, as well as his/her evaluation of the relationship to the study treatment. The 
signed form must be sent (preferably by email otherwise by fax) to Transgene immediately. 
The SAE form must be completed in English. 
Follow-up information (e.g., complications or progression of the initial SAE) must be notified 
to Transgene by the Investigator within the same time frame as the occurrence by using a new 
“SAE form” with the box “follow-up” ticked and sent to the Transgene.  
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated and whether the patient continued or withdrew his/her consent. 
 
Transgene or its representative may request further information as needed. 
 
All SAEs will be followed to resolution or stabilization. 
 
Notification to Regulatory Authorities / Gene Therapy Bodies / Ethics Committee 
Transgene or its representative will be responsible for reporting of SUSAR and any other SAEs 
to Regulatory Authorities, IEC(s) / IRB(s) and Gene Therapy Bodies as per local regulation. In 
case of a SUSAR, Transgene or its representative will inform all investigators involved in the 
study that such an event has been reported.  
The Investigator is responsible for informing local Ethics Committees, IRB(s) of SUSARs, any 
other SAEs, and any follow-up information as per local regulations. 
Transgene or its representative is responsible for ensuring that all AEs and SAEs that are 
observed or reported during the study are collected and reported to the FDA in accordance with 
CFR 312.32 (IND Safety Reports). 
 
Special situations 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. 
For this study, any dose of IMP greater than the assigned dose, and considered excessive and 
medically important by the Investigator, will be considered an overdose. 
 
All occurrences of overdose must be reported as SAEs (see Section 8.2.3). 
In the event of an overdose, the Investigator or treating physician should: 
• Contact the Medical Monitor immediately 
• Closely monitor the participant for AEs/SAEs and laboratory abnormalities  
• Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF 
 
Decisions regarding dose interruptions or modifications secondary to an overdose will be made 
by the Investigator in consultation with the Medical Monitor based on the clinical evaluation of 
the participant. 
 

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Any overdose should be reported to Transgene within 24 HOURS and documented and 
followed-up using an “Overdose form”. In addition, any associated symptoms should be 
reported as an AE or SAE. 
 
Other safety considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiogram, CT-scan, any other potential safety assessment required or not required by 
protocol should also be recorded as a non-serious or serious AE, as appropriate, and reported 
accordingly. 
 
Laboratory values, vital signs, physical findings and other safety 
data 
Laboratory tests results will be recorded on the laboratory results forms of the eCRF. 
Clinically relevant abnormal laboratory or tests results, clinically relevant abnormal findings in 
vital signs measurements, physical examinations or ECGs will be reported by the Investigator 
and followed until normal, stabilization or back to baseline value or until the safety follow-up 
visit if they are not related to the IMP. If related to the IMP, they should be followed even after 
the safety follow-up visit (see Section 8.2). 
Any laboratory result abnormality fulfilling the criteria for a serious adverse event (SAE) 
should be reported as such, in addition to being recorded as an AE on the eCRF. 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., meeting 
one or more of the following conditions, should be recorded as a single diagnosis on the adverse 
event form in the eCRF: 
• accompanied by clinical symptoms 
• leading to a change in study medications (e.g., interruption or permanent discontinuation) 
• requiring corrective treatment or clinical management 
 
Translational research and exploratory evaluations 
Mutational load and impact of vaccination on tumor mutational profile; specifically, tumor 
exome and transcriptome sequencing prior to initiation of treatment will allow identification of 
tumor specific mutations and their respective level of expression in tumor tissue. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9. STATISTICAL METHODS PLANNED AND SAMPLE SIZE 
9.1. Data sets analyzed 
 
Screening period 
All patients having signed the ICF will be considered as screened patients and included in the 
screening population (SCR). The percentage of patients not treated afterwards and the 
corresponding reason, will be analyzed. Available data from screen failed patients will be listed 
separately and presented according to the statistical plan. 
 
Treatment period 
Patients will be enrolled in separate cohorts at the time of treatment initiation according to: 
• Cohort A: patients develop an asymptomatic relapse defined on the basis of progressive 
serial elevations of serum CA-125 (GCIG criteria) or documentation of low volume 
radiological disease with CA-125 > Upper Limit of Normal (ULN). Low volume 
radiological disease is defined as radiologically visible disease excluding intra-hepatic or 
intra-splenic metastases, ascites or pleural effusion thought to require drainage. 
• Cohort B: patients develop an asymptomatic relapse with measurable disease excluding 
intra-hepatic or splenic metastases, ascites or pleural effusion thought to require drainage, 
whatever serum CA-125 level and for whom further treatment is not planned within 2 
months. Longest diameter on CT-scan must not exceed 2 cm for non-nodal lesions and 2.5 
cm in the short axis for nodal lesions. 
 
Safety Analysis Set (SAF): all patients included and who received at least one dose of TG4050 
will be included in the SAF. This is the primary dataset for safety analyses. 
CCI
CCI

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Evaluable Safety Set (ESAF): first 3 patients in SAF who completed the first 6 weeks of 
treatment or discontinued due to a DLT. Patients who are not evaluable for safety analysis 
during the run-in phase, or who are withdrawn for other reasons than toxicity, will be replaced. 
 
Evaluable Per-Protocol Set (EPP): all included patients in each cohort without any major 
protocol deviation who received at least the 6 first weekly injections of TG4050 corresponding 
to the treatment induction phase and have at least two baseline and two post-baseline 
evaluations of CA-125 and one baseline and one post-baseline CT-scan or MRI. 
 
Modified Evaluable Per-Protocol (mEPP): patients from EPP in each cohort who are evaluable 
for immune response meaning at least one pre-dose evaluation and one post-baseline 
evaluation. 
 
9.2. Determination of sample size 
No formal sample size calculation is planned. 
9.3. Study endpoint 
 
Primary endpoint 
Adverse events will be assessed throughout the treatment period and graded according to NCI 
CTCAE version 5. 
 
Secondary endpoints 
• Failure to provide rate: percentage of patients for whom TG4050 cannot be provided and 
the reason for not being able to provide the vaccine will be recorded. 
• Failure to treat rate: percentage of patients who cannot receive TG4050 and the reason that 
prevent patient from being treated. 
• CA-125 doubling time and half-life as appropriate 
• Time to normalization of CA-125 
• Response according to GCIC criteria 
• Time to measurable relapse in Cohort A and Time to progression in Cohort B per RECIST 
1.1  
• Tumor response according to RECIST 1.1 
 
Translational research 
The following exploratory endpoints will be investigated: 
• 
 
 
 
 
  
 
 
 
 
 
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• Quantification of tumor and immune related biomarkers  
9.4. Statistical and analytical plans 
 
Safety analyses for the treatment period 
All safety analyses will be performed and summarized in the SAF. Safety analyses will also be 
conducted in each cohort of treated patients. 
 
Adverse events 
AE summaries will include all TEAEs corresponding to AEs that have started on or after the 
day of first study treatment administration or that have worsened on or after first TG4050 
administration and starting no later than 30 days after the date of last study treatment 
administration. All AEs, significant AEs, AEs leading to discontinuation of study treatment, 
severe AEs (Grade 3 or 4) and serious AEs (SAE) will be listed and summarized by System 
Organ Class (SOC) and Preferred Term (PT), intensity (based on the NCI CTCAE grades, 
relationship to TG4050).  
Written narratives will be produced for all SAEs and unexpected or other significant AEs that 
are judged to be of special interest because of their clinical importance. 
Adverse events/SAEs occurring after signing the Informed Consent Form (ICF) but before 
starting study treatment, including those observed in patients screened but not included will be 
listed separately from those occurring after treatment start. 
SAEs occurring more than 30 days after administration of the last dose of TG4050 and 
evaluated by the investigator as related to TG4050 will be listed separately.  
 
Fatal Events 
All fatal events will be listed and summarized by System Organ Class (SOC) and Preferred 
Term (PT). The nature of the event leading to death should be recorded. Sudden/unexplained 
death will be coded as “death”.  
Fatal events will be summarized by presenting the number and percentage of patients who died. 
Data will be presented by SOC and PT using MedDRA coding.  
Fatal events occurring after signing the Inform Consent Form (ICF) but before starting study 
treatment in patients screened but not included will be listed separately from those occurring 
after treatment start. 
 
Laboratory abnormalities 
The summaries will include all laboratory assessments collected from baseline assessment until 
30 days after treatment discontinuation. All laboratory assessments will be listed and those 
collected during 30 days after study treatment discontinuation will be flagged in the listings. 
All laboratory values will be converted into SI units and will have a severity grade calculated 
using appropriate common terminology criteria for AEs (NCI-CTCAE, version 5). A listing of 
laboratory values will be provided by laboratory parameter and patient. A separate listing will 
display notable laboratory abnormalities (i.e., newly occurring CTCAE Grade 3 or 4 laboratory 
toxicities). The frequency of these notable laboratory abnormalities will be displayed by 
parameter. The shift tables using CTCAE grades to compare baseline to the worst post-baseline 
value will be produced for all relevant safety measures as described in the statistical analysis 

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plan. Note that for parameters with two directions abnormalities (hypo/hyper), two tables will 
be presented. 
 
Other safety data 
Other safety data (e.g., vital signs, electrocardiogram) will be listed, notable values will be 
flagged, and any other information collected will be listed as appropriate. Any statistical 
procedures performed in order to explore the data will be used only to highlight any interesting 
comparisons that may warrant further consideration. 
 
Efficacy analyses for the treatment period 
The analysis of the efficacy endpoints will be performed on the evaluable population (EPP) for 
efficacy in each cohort of treated patients. 
CA-125 doubling time and half-life as appropriate, time to normalization and response 
according to GCIG as well as time to measurable relapse or progression will be analyzed. 
Time to measurable relapse in Cohort A and Time to progression in Cohort B per RECIST 1.1 
Tumor response according to RECIST 1.1. will be analyzed. 
 
Translational research 
A statistical analysis plan dedicated to translational research will be provided separately. 
9.5. Methods of analysis 
 
General considerations 
Statistical summaries will be produced using SAS® software version 9.4 or higher. Continuous 
variables will be described using the number of observations (N), arithmetic mean (Mean), 
standard deviation (sd), minimum (MIN), median (Median), and maximum (MAX). Means will 
be further described with 95% confidence intervals (CIs) where appropriate. Categorical 
variables will be summarized by frequency (N) and percentage (%). Proportions will be 
estimated with their 95% CIs when appropriate. 
 
Disposition of patients 
The number of screen failure patients and reasons for screen failure will be summarized. A 
patient listing will be provided with the reason of screen failure. 
 
Demographic and baseline characteristics 
Baseline demographics and disease characteristics data will be listed and summarized. 
Qualitative data will be summarized by means of contingency tables, and quantitative data will 
be summarized by appropriate descriptive statistics (mean, standard deviation, median, Q1, Q3, 
minimum, and maximum). 

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Treatments 
9.5.4.1. 
Prior anti-cancer therapies 
Prior antineoplastic therapies will be listed and summarized (surgery, chemotherapy, other 
therapies).  
 
The SAF set will be used for all summaries and listings of prior anti-cancer therapies and results 
will also be provided for each cohort of treated patients. 
9.5.4.2. 
Study treatment 
Exposure to TG4050 will be provided by listing and summarizing the number of injections and 
the duration of treatment. 
The SAF will be used for all summaries and listings of study treatment. Analyses will be 
displayed separately for each cohort of treated patients. 
The number of patients with dose omission will be presented along with reasons for the dose 
omission. 
9.5.4.3. 
Concomitant medications 
Medications and/or non-drug therapies taken by the patient during the month prior to start of 
the study treatment, as well as all medications and significant non-drug therapies taken during 
the course of the study up to 30 days after the last study treatment administration, will be 
collected with their start date and end date, reason for prescription, route of administration and 
dose. 
The concomitant medications (i.e., ongoing at the start of study treatment or taken during the 
course of the study) will be coded using WHO Drug dictionary including the Anatomical 
Therapeutic Chemical (ATC) classification and will be listed and summarized by active 
ingredient by means of frequency counts and percentages. 
The SAF will be used for all above mentioned concomitant medication tables. 
9.6. Protocol deviations 
Any protocol deviations impacting statistical analyses will be classified as major and the list 
will be described in the statistical analysis plan in order to determine the evaluable population 
for efficacy. All these protocol deviations for included patients will be presented by patient in 
data listings with a distinction between deviations at inclusion and deviations during the study. 
The number of patients with at least one major protocol deviation will be summarized by type 
and overall with a distinction between deviations at inclusion and deviations during the study. 
 
 
10. CHANGES IN THE CONDUCT OF THE STUDY 
10.1. 
Protocol amendments 
Changes to this protocol will be performed through amendments issued by Transgene after 
mutual agreement of the Investigator(s) and Transgene. Both the Investigator(s) and Transgene 

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will sign the amendments. When applicable, amendments are submitted to Health Authorities 
and the Independent Ethics Committee (IEC(s) and any other committees by Transgene or the 
sub-contractor or the Coordinating / Principal Investigator according to local regulations. 
Authorization / approval will be required before implementation of any change to the protocol 
which could significantly affect the safety of patients, the scope of the investigation, the 
scientific quality of the study or any other aspect of the study. Other changes will be provided 
when required by local laws to IEC(s) and any other committees for information only. 
An amendment intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately. Such an amendment must be notified as soon as possible to 
Regulatory Authorities IEC(s) and any other committees as locally required for authorization / 
approval. 
10.2. 
Premature termination or suspension of the study 
During the safety run-in phase, the study may be suspended and an IDMC ad-hoc meeting 
immediately called if at least one of the following events occur: 
- 
any grade ≥3 toxicity that is at least possibly related to TG4050, with the following 
exception: pre-existing grade 2 fatigue at baseline that would worsen up to grade 3 
- 
any death. 
Beyond the safety run-in phase, the study may be suspended or terminated under any of the 
following circumstances: 
- 
Sponsor’s decision 
- 
Health Authorities’ decision 
- 
Any death, unrelated to progressive disease, which occurs within 30 days after TG4050 
administration 
- 
IDMC recommendation in case of a safety concern. However, in this case, the final 
decision as to whether or not to continue the study will be taken by Transgene. 
 
If the study needs to be terminated, Transgene and the Investigator will assure that adequate 
consideration is given to the protection of the patients. Transgene will notify the Health 
Authorities and the IEC(s)/IRB(s), any other committees of the premature study termination 
according to local regulations. 
 
Should the study be prematurely stopped or put “on-hold” upon Health Authorities’ decision, 
Transgene will inform immediately the Investigators in written including measures to be 
implemented. 
If the study is prematurely discontinued, all study data must be returned to Transgene. In 
addition, the site must conduct final disposition of all unused study drugs in accordance with 
Transgene procedures for the study. 
 
 

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11. ETHICAL CONSIDERATIONS 
11.1. 
Independent Ethics Committee/Institutional Review Board 
Before starting the study, the protocol, the written patient information sheet and informed 
consent form, and any other document specifically requested must be reviewed and approved 
by an IEC complying with the requirements of relevant local law. 
Before enrollment of patients, Transgene must obtain from the IEC(s) / IRB(s) a written 
authorization / approval and the list of members having participated in the meeting including 
their qualification. 
 
In addition, IEC / IRB written approval must be obtained by Transgene for protocol amendment 
as described in Section 10.1. 
11.2. 
Informed consent 
The Investigator or his/her delegate will obtain a voluntary written consent from each patient 
after an appropriate explanation of the aims, methods, anticipated benefits, risks and any other 
aspect of the study relevant to the patient’s decision to participate. Consent forms and all verbal 
study related information must be in a language fully comprehensible to the prospective patient. 
Patients will be informed that they are free not to participate in the study and that they may 
withdraw consent to participate at any time. They will be told which alternative treatments are 
available if they refuse to take part and that such refusal will not prejudice future treatment. 
Patients will be informed that their records, including medical history, may be examined by 
competent authorities and authorized persons but that personal information will be treated as 
strictly confidential and will not be publicly available. 
A written “patient information sheet” will be given to each patient to complete the verbal 
information. This written form should be reviewed orally with the patient. Patient must be given 
ample opportunity to inquire about details of the study. 
The “patient information sheet” will explain that the data collected for this study will be stored 
in a computer database, with confidentiality maintained in accordance with national data 
legislation (for instance, the European General Data Protection Regulation for European 
countries).  
 
Informed consent shall be documented by the use of a written consent form approved by the 
IEC and signed and dated by the Investigator and the patient before any exposure to a study-
related procedure, including screening tests for eligibility. Any new version of the ICF will be 
signed by all ongoing patients. 
 
A copy of each signed informed consent form must be given to the patient and to his/her legally 
authorized representative. The originals are filed at the study site in the Investigator Site File. 
11.3. 
Confidentiality of patient data 
The Investigator must assure that patients’ anonymity is maintained and that their identities are 
protected from unauthorized parties. On eCRFs or other documents collected by Transgene or 

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its representative, patients should not be identified by their names, but by an identification code 
system.  
 
For European countries:  
Confidentiality of patients’ medical records will be maintained in accordance with the 
applicable data privacy laws such as, for instance, the European General Data Protection 
Regulation (Regulation EU 2016/679 of 27 April 2016 on the protection of natural persons 
regarding the processing of personal data and on the free movement of such data). 
 
The Investigator should keep a patient identification log showing codes, names and addresses 
of all patients consented. A copy of this log without names and addresses will be filed at 
Transgene after study completion. 
11.4. 
Independent Data Monitoring Committee 
 
Responsibilities of the Independent Data Monitoring Committee 
Members of the IDMC will be responsible for reviewing primarily the safety data as well as the 
conduct of the study.  
 
The IDMC will review the safety data of the 3 first patients from Cohort A or B at the end of 
the safety run-in phase of the treatment period. 
In addition to the review of the first 3 patients, the IDMC will review safety data of all patients 
included every 3 months during the first year and every 6 months thereafter. 
Safety reviews by the IDMC may also be called by Transgene on an ad hoc basis upon 
necessity. 
 
Safety reviews to investigators 
The outcome(s) of any safety review conducted by the IDMC during the study will be shared 
with all participating investigators including corrective measures, if appropriate. Timelines of 
communication to participating investigators will be specified in the IDMC charter. Written 
and signed recommendations from the IDMC will be available within 24 hours.  
 
Further details on the organization, roles, and responsibilities of this committee will be 
established in an Independent Data Monitoring Committee charter signed by its members. 
 
 
12. REGULATORY CONSIDERATIONS 
 
This study will be conducted in accordance with: 
- The updated Declaration of Helsinki adopted by the World Medical Association, 
- The ICH E6 (R2) (International Conference on Harmonization) Good Clinical Practice 
(GCP) guidelines, and 
- The local regulatory requirements. 

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12.1. 
Regulatory approval / authorization 
The regulatory authorization / approval for conducting the study will be obtained from 
Regulatory Authorities in accordance with local regulatory requirements. Additional 
authorizations / approvals will be obtained from the national gene therapy committee, as 
required. All approvals must be obtained before a patient is exposed to a study-related 
procedure, including baseline screening tests for eligibility. 
12.2. 
Investigators’ obligations 
Before the study starts, the Investigator shall provide Transgene with his/her curriculum vitae 
and complete a list giving the names, functions and authorized activities of all persons who will 
exercise any kind of responsibility in carrying out of the study. CVs of these people will also 
be collected. 
 
The Investigator also provides to the site staff appropriate training. The staff training will be 
documented in the Investigator Site File. 
 
The Investigator ensures supervising any individual or party to whom trial-related duties and 
functions conducted at the site have been delegated. When trial-related duties or functions are 
delegated to parties, the investigator should ensure the individual or party is qualified to 
perform the delegated tasks and should implement procedures to ensure the integrity of the 
trial-related duties and functions performed and any data generated. 
 
The Investigator ensures the quality of the study through strict observance of the protocol, Good 
Clinical Practice and local regulations. Investigator must ensure that the study has been 
authorized / approved by all Regulatory Authorities, IEC and any other committees prior to 
enrolling patients and on an ongoing basis as locally required. 
Investigator is required to obtain written informed consent from each patient prior a patient is 
exposed to a study-related procedure, including baseline screening tests for eligibility. 
12.3. 
Insurance 
Transgene certifies having taken out a civil liability insurance policy covering liability with 
regard to the participants in this study. 
 
 
13. QUALITY CONTROL AND QUALITY ASSURANCE 
13.1. 
Monitoring 
The monitor will contact and visit the Investigator periodically to evaluate study progress and 
protocol compliance with the first visit occurring as soon as possible after the first patient 
inclusion. Intervals may be adjusted according to patient accruals, protocol changes or site 
performance. Remote monitoring is allowed in the respect of maintaining confidentiality and 
integrity of medical data. 

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Monitoring activities are based on instructions given within the Monitoring Plan and could be 
complemented by Central monitoring activities. 
During the visit, the Investigator and any study staff member will co-operate with the monitor 
to ensure that any problems are resolved. 
13.2. 
Audit and inspection 
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
patients have been adequately protected, and that all data relevant for the evaluation of the IMP 
have been processed and reported in compliance with GCP and applicable regulatory 
requirements. 
Transgene is responsible for making sure that both his representatives (monitor, clinical 
research assistant) and the investigator fulfil their requirements as specified by the GCP 
guidelines. The audit can be made internally at Transgene and at the investigational site or at 
the Services Provider. Possibility to have a direct access to all study documentation is 
compulsory. The practical conditions for the audit will be discussed between the investigator 
and the Clinical Quality Assurance Department.  
The Health Care Authorities may inspect any investigational site or Transgene during the course 
of the study or following its completion, to verify the conduct of the study and quality of the 
data. The investigator will provide direct access to source documents. 
After appropriate notification, the Investigator will make all study-related source data and 
documents available to a quality assurance auditor mandated by Transgene, or to domestic or 
foreign regulatory inspectors. 
 
 
14. DATA HANDLING AND RECORD KEEPING 
14.1. 
Source data and documents 
Source data are all information available in original source document or certified copies of 
source document of any clinical findings, observations, or other activities that are necessary for 
the reconstruction and evaluation of the study. 
The Investigator will record at least the following information in the source documents for all 
consented patients: date of birth, gender, medical history, reference to the study, visit dates, 
study treatment administrations, concomitant medications, evaluation criteria and nature of 
adverse events with date of start and end and relationship to study treatment. The location of 
each source data will be identified on a dedicated form. 
 
If computerized systems are used to record subjects’ source data (i.e. subjects’ electronic source 
documents), the following criteria should be met: 
• documented evidence that the computer system has been validated, 
• the system provides adequate security to ensure that only authorized people can access the 
system (log in / password) to enter/change data, 
• the system allows audit trail of entries / changes, 
• existence of a back-up system, 
• existence of data security in case of a system break down, 

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• the users of the system are trained to the system, 
• a user list is maintained, 
• existence of a written procedure covering these aspects, 
• servers containing data are physically protected, 
• if an electronic signature is used: 
- 
the log in and password are entered upon signature 
- 
the electronic signature is timestamped 
• if no electronic signature is in place, the PI agrees to print out subjects’ source data 
periodically and to sign the printouts. 
 
The Investigator will permit study-related monitoring, audit(s), and regulatory inspection(s), 
with a direct access to all the required source documents each time it is necessary provided that 
patient confidentiality is protected. 
14.2. 
Case report forms 
Electronic Data Capture (EDC) will be used for this study, meaning that all CRF data will be 
entered in electronic forms at the investigational site for each screened patient. 
All data must be entered in English by the investigator. 
The eCRFs should always reflect the latest observations on the patients participating in the 
study. Therefore, the eCRFs are to be completed without any delay after the patient’s visit.  
The Investigators must verify that all data entries in the eCRFs are accurate and correct. If some 
assessments are not done, or if certain information is not available, not applicable, or unknown, 
the Investigators should indicate this in the eCRF. The Investigators will be required to 
electronically sign off all the clinical data collected. 
The Monitors will review the eCRFs and evaluate them for completeness and consistency. The 
eCRF will be compared with the source documents to ensure that there are no discrepancies.  
All entries, corrections, and alterations are to be made by the Investigator or his/her delegate. 
Once clinical data have been submitted, corrections to the data fields will be audit trailed, 
meaning that the reason for change and the name of the person who performed the change, 
together with time and date, will be logged. Roles and rights of the site personnel responsible 
for entering the clinical data into the eCRF will be determined in advance and documented on 
the “delegation form”. 
If additional corrections or confirmation are needed, the Monitors, Data Manager(s) or 
authorized Transgene’s medical monitors will raise a query. 
 
After database lock, the Principal Investigator will receive a copy of the patient eCRF data for 
archiving at the investigational site. 
 
 
15. CLINICAL STUDY REPORT AND PUBLICATION 
15.1. 
Clinical study report 
All relevant data will be reported in a clinical study report which will be prepared by 
Transgene/CRO and submitted for comments and signature to the coordinating / principal 

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Investigator. The final report is used for regulatory purposes by Transgene according to local 
regulations and provided to each Investigator once finalized. 
15.2. 
Confidentiality of study data 
Any information provided by Transgene, including nonclinical data, protocols, eCRFs, verbal 
and written information, and results of the study will be kept strictly confidential and confined 
to the clinical personnel involved in conducting this study, and no disclosure shall be made 
except in accordance with any right of publication granted to the Investigator by Transgene. 
15.3. 
Publication policy 
The results of this study may be published or presented at scientific meetings. If this is 
envisaged, the coauthors agree to submit all manuscripts or abstracts to Transgene prior to 
scientific meeting or journal submission allowing for reasonable time to review, consistent with 
Transgene policy. This allows Transgene to protect proprietary information and to provide 
medical/scientific review. For intellectual property protection purposes, Transgene can request 
the coauthors to delay publication or presentation of results. 
 
Consistent with Good Publication Practices (GPP2), authorship is to follow the criteria outlined 
by the International Committee of Medical Journal Editors (ICMJE), and/or follow the policies 
outlined by the journal or scientific congress. Financial support for medical writing assistance 
or travel provided to the authors is also to be acknowledged. 
 
In accordance with consistent editorial practice, Transgene supports the publication of primary 
study results from multicenter studies in their entirety prior to any secondary analyses. 
Publication of individual center data unless ancillary study / data is discouraged. A publication 
in which the contribution of Transgene’s personnel exceeded that of conventional monitoring 
will be considered for co-authorship provided all other criteria of ICMJE are met. 
 
 
16. ARCHIVING 
16.1. 
Investigator site file 
In accordance with the ICH GCP standards, the Investigator is responsible for on-site storage 
and maintenance of all records pertaining to the study for the maximum period of time required 
by local requirements. 
No study site document may be destroyed without prior written agreement between the 
Investigator and Transgene. Transgene must be notified if the Investigator assigns the study 
documentation to another party or moves it to another location. 
 
If the Investigator cannot guarantee this archiving requirement on site for any or all of the 
documents, special arrangements must be made between the Investigator and Transgene to store 
the documents in a sealed container off-site so they can be returned sealed to the Investigator 
in case of an audit/inspection. 

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16.2. 
Trial master file 
Transgene will archive the trial master file (TMF) in accordance with GCP and applicable 
regulatory requirements and will inform the Investigator when the archiving of the study 
documentation is no longer required. 
 
 

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17. APPENDICES 
 
APPENDIX I: PERFORMANCE STATUS (ECOG) SCALE 
APPENDIX IIA STUDY FLOW CHART (screening period) 
APPENDIX IIB: STUDY FLOW CHART (treatment period) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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18. REFERENCES 
 
Arend R.C., Londono A.I., Montgomery A.M., Smith H.J., Dobbin Z.C., Katre A.A., Martinez A., Yang E.S., 
Alvarez R.D., Huh W.K., Bevis K.S., Straughn J.M., Jr., Estes J.M., Novak L., Crossman D.K., Cooper 
S.J., Landen C.N. and Leath C.A., 3rd. "Molecular Response to Neoadjuvant Chemotherapy in High-
Grade Serous Ovarian Carcinoma." Mol Cancer Res. (2018) 16(5): 813-824. 
 
Bendjama K. and Quemeneur E. "Modified Vaccinia virus Ankara-based vaccines in the era of personalized 
immunotherapy of cancer." Hum Vaccin Immunother. (2017) 13(9): 1997-2003. 
 
Braun S., Schindlbeck C., Hepp F., Janni W., Kentenich C., Riethmuller G. and Pantel K. "Occult tumor cells in 
bone marrow of patients with locoregionally restricted ovarian cancer predict early distant metastatic 
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Burger R.A., Brady M.F., Bookman M.A., Fleming G.F., Monk B.J., Huang H., Mannel R.S., Homesley H.D., 
Fowler J., Greer B.E., Boente M., Birrer M.J., Liang S.X. and Gynecologic Oncology G. "Incorporation 
of bevacizumab in the primary treatment of ovarian cancer." N Engl J Med. (2011) 365(26): 2473-2483. 
 
Burger R.A., Enserro D., Tewary K.S., Brady M.F., Bookman M.A., Fleming G.F., Huang H.Q., Homesley H.D., 
Fowler J., Boente M., Randall L.M., Chan J.K., Ferris J.S., DiSaia P.J., Copeland L.J., Mannel R.S., 
Birrer M.J. and Monk B.J. "Final overall survival (OS) analysis of an international randomized trial 
evaluating bevacizumab (BEV) in the primary treatment of advanced ovarian cancer: A NRG 
oncology/Gynecologic Oncology Group (GOG) study." Journal of Clinical Oncology. (2018) Volume 
36( Issue 15 suppl :5517.). 
 
Elizaga M.L., Vasan S., Marovich M.A., Sato A.H., Lawrence D.N., Chaitman B.R., Frey S.E. and Keefer M.C. 
"Prospective surveillance for cardiac adverse events in healthy adults receiving modified vaccinia ankara 
vaccines: a systematic review." PLoS One. (2013) 8(1): e54407. 
 
Gercel-Taylor C., Scobee J.J. and Taylor D.D. "Effect of chemotherapy on the mutation frequency of ovarian 
cancer cells at the HPRT locus." Anticancer Res. (2005) 25(3B): 2113-2117. 
 
Masoodi T., Siraj S., Siraj A.K., Azam S., Qadri Z., Parvathareddy S.K., Tulbah A., Al-Dayel F., AlHusaini H., 
AlOmar O., Al-Badawi I.A., Alkuraya F.S. and Al-Kuraya K.S. "Genetic heterogeneity and evolutionary 
history of high-grade ovarian carcinoma and matched distant metastases." Br J Cancer. (2020) 122(8): 
1219-1230. 
 
O'Donnell T., Christie E.L., Ahuja A., Buros J., Aksoy B.A., Bowtell D.D.L., Snyder A. and Hammerbacher J. 
"Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer." BMC Cancer. 
(2018) 18(1): 87. 
 
Paracchini L., Beltrame L., Grassi T., Inglesi A., Fruscio R., Landoni F., Ippolito D., Delle Marchette M., Paderno 
M., Adorni M., Jaconi M., Romualdi C., D'Incalci M., Siravegna G. and Marchini S. "Genome-wide 
Copy-number Alterations in Circulating Tumor DNA as a Novel Biomarker for Patients with High-grade 
Serous Ovarian Cancer." Clin Cancer Res. (2021) 27(9): 2549-2559. 
 
Pereira E., Camacho-Vanegas O., Anand S., Sebra R., Catalina Camacho S., Garnar-Wortzel L., Nair N., Moshier 
E., Wooten M., Uzilov A., Chen R., Prasad-Hayes M., Zakashansky K., Beddoe A.M., Schadt E., Dottino 
P. and Martignetti J.A. "Personalized Circulating Tumor DNA Biomarkers Dynamically Predict 
Treatment Response and Survival In Gynecologic Cancers." PLoS One. (2015) 10(12): e0145754. 
 
Perren T.J., Swart A.M., Pfisterer J., Ledermann J.A., Pujade-Lauraine E., Kristensen G., Carey M.S., Beale P., 
Cervantes A., Kurzeder C., du Bois A., Sehouli J., Kimmig R., Stahle A., Collinson F., Essapen S., 
Gourley C., Lortholary A., Selle F., Mirza M.R., Leminen A., Plante M., Stark D., Qian W., Parmar M.K., 
Oza A.M. and Investigators I. "A phase 3 trial of bevacizumab in ovarian cancer." N Engl J Med. (2011) 
365(26): 2484-2496. 
 
Pujade-Lauraine E., Ledermann J.A., Selle F., Gebski V., Penson R.T., Oza A.M., Korach J., Huzarski T., Poveda 
A., Pignata S., Friedlander M., Colombo N., Harter P., Fujiwara K., Ray-Coquard I., Banerjee S., Liu J., 
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therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation 
(SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial." Lancet Oncol. 
(2017) 18(9): 1274-1284. 
 
Quoix E., Lena H., Losonczy G., Forget F., Chouaid C., Papai Z., Gervais R., Ottensmeier C., Szczesna A., 
Kazarnowicz A., Beck J.T., Westeel V., Felip E., Debieuvre D., Madroszyk A., Adam J., Lacoste G., 
Tavernaro A., Bastien B., Halluard C., Palanche T. and Limacher J.M. "TG4010 immunotherapy and 
first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part 
of a randomised, double-blind, placebo-controlled, phase 2b/3 trial." Lancet Oncol. (2016) 17(2): 212-
223. 
 
Rustin G.J., van der Burg M.E., Griffin C.L., Guthrie D., Lamont A., Jayson G.C., Kristensen G., Mediola C., 
Coens C., Qian W., Parmar M.K., Swart A.M., Mrc O.V. and investigators E. "Early versus delayed 
treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial." Lancet. (2010) 
376(9747): 1155-1163. 
 
Tosch C., Bastien B., Barraud L., Grellier B., Nourtier V., Gantzer M., Limacher J.M., Quemeneur E., Bendjama 
K. and Preville X. "Viral based vaccine TG4010 induces broadening of specific immune response and 
improves outcome in advanced NSCLC." J Immunother Cancer. (2017) 5(1): 70. 
 
Vollebergh M.A., Jonkers J. and Linn S.C. "Genomic instability in breast and ovarian cancers: translation into 
clinical predictive biomarkers." Cell Mol Life Sci. (2012) 69(2): 223-245. 
 
Zhang L., Conejo-Garcia J.R., Katsaros D., Gimotty P.A., Massobrio M., Regnani G., Makrigiannakis A., Gray 
H., Schlienger K., Liebman M.N., Rubin S.C. and Coukos G. "Intratumoral T cells, recurrence, and 
survival in epithelial ovarian cancer." N Engl J Med. (2003) 348(3): 203-213. 
 
Zitzmann-Roth E.M., von Sonnenburg F., de la Motte S., Arndtz-Wiedemann N., von Krempelhuber A., Uebler 
N., Vollmar J., Virgin G. and Chaplin P. "Cardiac safety of Modified Vaccinia Ankara for vaccination 
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APPENDIX I 
 
PERFORMANCE STATUS (ECOG) SCALE 
 
 
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 self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
 
3:  Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
 
4:  Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair.  
 

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APPENDIX II-A: STUDY FLOW-CHART 
 
Screening-period 
 
 
Study entry  
(At least six months after first-line 
CT) 
Follow-up in CR patients  
Asymptomatic relapse 
ICF 
X 
 
 
History of HGSC, relevant medical history 
X 
 
 
Inclusion/exclusion criteria check 
   X(1) 
 
X 
Physical examination 
X 
X 
X 
Concomitant medications 
X 
X 
X 
HCV, HBsAg 
X 
 
 
Blood sampling (for sequencing/central 
laboratory) 
X 
 
 
Archived tumor tissue (for sequencing/central 
laboratory) 
X 
 
 
CA-125 concentration 
X 
X 
   X(2) 
ctDNA measurement 
X 
X 
 
Imaging 
   X(3) 
    X (4) 
   X(2) 
Request for clinical supplies 
 
 
X 
 
(1) Check that complete response has been achieved. If a suspicious but indeterminate nodule is identified at study entry, repeat imaging should be obtained 
3 months after (+/- 2 weeks) to determinate whether the nodule is malignant. Alternatively, a biopsy may be obtained. 
(2) Cohort A: CA-125 ≥ 2 x ULN on 2 occasions at least 1 week apart; or low volume radiological disease and CA-125 > ULN  
 Cohort B: patient asymptomatic with measurable disease whatever serum CA-125 level and for whom further treatment is not planned within 2 months. 
(3) Imaging performed within 28 days prior to study entry visit can be used 
(4) Imaging indicated if symptoms or clinical signs occur or if CA-125 increases or as current medical practice 
 
 
 
 
 
 

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APPENDIX II B: STUDY FLOW-CHART 
Treatment period 
 
 
Baseline 
First 6 weeks 
Beyond 6 weeks 
End of 
treatment 
visit 
Safety 
Follow-up 
visit 
 
Observation 
(6) 
  
≤ 21 days 
prior 
to 
treatment 
start 
≤ 7 days 
prior 
to 
treatment 
start 
D1 
D8  
(W1) 
 +/- 1 day 
D15 
(W2)  
+/- 1 day 
D22 
 (W3) 
 +/- 1 day 
D29 
(W4) 
+/- 1 day 
D36 
(W5)  
+/- 1 day 
D43 
(W6)  
+/- 1 day 
Q3 
weeks  
+/- 7 days 
Q9 
weeks  
+/- 7 days 
Within 
7 
days 
after 
treatment 
stop 
At least 30 days 
after last study 
treatment 
administration 
(+ 14 days) 
Q9weeks 
+/- 7 days 
TG4050 
Administration (9) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Inclusion/exclusion 
criteria check 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Current medical 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Performance status 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
ECG  
X 
 
 
 
 
X 
 
 
X 
X(3) 
 
X 
 
 
AEs/SAEs 
reporting(7) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
CBC 
 
X 
 
X(8) 
X(8) 
X(8) 
X(8) 
X(8) 
X(8) 
X(8) 
 
X 
 
 
Biochemistry 
 
X 
 
X(8) 
X(8) 
X(8) 
X(8) 
X(8) 
X(8) 
X(8) 
 
X 
 
 
Blood samples + 
cytapheresis for 
translational 
research 
 
 
   X(1) 
 
X(1) 
 
X(1) 
 
 
X(1) 
X(1) 
X(1) 
 
 

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Baseline 
First 6 weeks 
Beyond 6 weeks 
End of 
treatment 
visit 
Safety 
Follow-up 
visit 
 
Observation 
(6) 
 
  
≤ 21 days 
prior to 
treatment 
start 
≤ 7 days 
prior to 
treatment 
start 
D1 
D8  
(W1) 
 +/- 1 day 
D15 
(W2)  
+/- 1 day 
D22 
 (W3) 
 +/- 1 day 
D29 
(W4) 
+/- 1 day 
D36 
(W5)  
+/- 1 day 
D43 
(W6)  
+/- 1 day 
Q3 
weeks  
+/- 7 days 
Q9 
weeks  
+/- 7 days 
Within 7 
days after 
treatment 
stop 
At least 30 days 
after last study 
treatment 
administration 
(+ 14 days) 
Q9 weeks 
+/- 7 days 
Tumor samples for 
translational 
research 
 
 
 
 
 
 
 
 
 
 
 
X(2) 
 
 
CA-125 
concentration 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
X 
Tumor assessment 
X(4) 
 
 
 
 
 
 
 
X 
 
X(5) 
 
 
X 
 
(1) Blood samples for translational research will be collected at baseline, on 
, cytapheresis at baseline and on 
Day 64 or at the end of treatment visit if patient is withdrawn prior to Day 64. 
(2) Tumor samples for translational research will be collected at the time of clinical recurrence 
(3) ECG every 6 weeks up to Day 169, thereafter every 12 weeks 
(4) Imaging to be performed only if the previous imaging has been performed more than 4 weeks before treatment start. 
(5) Tumor assessment by imaging procedures will be performed on Day 43 and every 9 weeks thereafter 
(6) For patients who stopped study treatment before documentation of disease progression 
(7) AEs reported up to 30 days after last treatment, only SAEs related to IMP thereafter 
(8) CBC including RBC, Hb, WBC and differential, platelets & Biochemistry every week up to Week 6, then every 3 weeks up to Month 6 (Day190), thereafter every 12 
weeks 
(9) TG4050 will be administered up to a total of 20 injections or until disease progression justifying initiation of further treatment, unacceptable toxicity including occurrence 
of a dose-limiting toxicity, or patient withdrawal for any reason whichever occurs first. 
 
CCI