A Phase Ib/II Trial Evaluating the Combination of TG4001 and Avelumab in Patients With HPV-16 Positive Recurrent or Metastatic Malignancies.
Phase: PHASE1
Conditions: HPV-Related Carcinoma, HPV-Related Cervical Carcinoma, HPV-Related Anal Squamous Cell Carcinoma, HPV-Related Penile Squamous Cell Carcinoma, HPV-Related Vulvar Squamous Cell Carcinoma
Sponsor: Transgene

Clinical Study Protocol  
CONFIDENTIAL 
A phase Ib/II trial evaluating the combination of TG4001 and avelumab in 
patients with HPV-16 positive recurrent or metastatic malignancies  
Study phase: Ib/II 
PROTOCOL N° TG4001.12 
Final Version 10.0 / 06 December 2023 
EudraCT N°2016-002799-28 
NCT N°03260023
COORDINATING/ 
PRINCIPAL INVESTIGATOR: Name, title: 
 
Full address:  
 
 
 
SPONSOR: 
Transgene S.A. 
Boulevard Gonthier d'Andernach 
Parc d'Innovation - CS80166 
67405 Illkirch Graffenstaden Cedex - FRANCE 
PERSON TO CONTACT: 
 
 
 
 
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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INVESTIGATORS / STUDY ADMINISTRATIVE STRUCTURE 
 
NAMES AND CONTACT DETAILS 
Principal / Coordinating 
Investigator 
 
 
 
 
 
 
Centers / Investigators 
The complete Investigator list is available in the Investigator 
Site File and in the Trial Master File at Transgene 
 
 
Transgene’s Staff 
 
 
 
 
Chief Medical Officer 
Pharmacovigilance 
Physician 
Clinical Project Manager 
  
  
 
  
 
  
 
Transgene S.A. 
Boulevard Gonthier d'Andernach 
Parc d'Innovation - CS80166 
67405 Illkirch Graffenstaden Cedex - FRANCE 
 
 
 
 
 
 
 
Statistician 
 
 
  
 
 
 
 
 
A complete list of details for the Contract Research Organization (CRO), the central 
laboratory/ies and the independent review 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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DOCUMENT APPROVAL 
 
 
 
SPONSOR’S OFFICER(S) 
 
 
 
 
 
 
 
 
 
 
 
STATISTICIAN 
 
 
 
 
 
 
 
 
 
COORDINATING INVESTIGATOR 
 
 
 
 
 
 
 
 
 

Transgene / Confidential 
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SYNOPSIS 
 
 
Sponsor: Transgene 
Active substances: 
TG4001 
 
 
 
Avelumab 
Study Title 
A phase Ib/II trial evaluating the combination of TG4001 and avelumab in patients with HPV-16 
positive recurrent or metastatic malignancies. 
Study N°: TG4001.12 
EudraCT N°: 2016-002799-28 
IND N°: 8147 
Coordinating / Principal Investigator: 
 
 
Investigational Center(s) / Country(ies): 
Phase Ib: 3 in France 
Phase II part 1: up to 20 in at least France, Spain and UK 
Phase II part 2: up to 25 in at least France, Spain, UK, Italy, and US 
Study Period: Q3 2017 – Q4 2024 
Clinical Phase: Ib/II 
Objectives 
Primary objectives: 
Phase Ib: To evaluate the safety and tolerability of the combination of TG4001 plus avelumab in 
patients with recurrent or metastatic HPV-16 positive advanced malignancies  
 
Phase II part 1: To evaluate the efficacy of TG4001 combined to avelumab in terms of Overall Response 
Rate (ORR) by using RECIST 1.1 in patients with recurrent or metastatic (R/M) HPV-16 positive 
advanced malignancies including oropharyngeal SCCHN 
 
Phase II part 2: To compare the Progression-Free Survival (PFS) of TG4001 in combination with 
avelumab vs avelumab alone in patients with recurrent or metastatic (R/M) HPV-16 positive advanced 
malignancies and without liver metastases at baseline. PFS will be evaluated based on RECIST 1.1.  
 
Secondary objectives: To evaluate the combination of TG4001 and avelumab with respect to: 
• 
Overall response rate (ORR) by using RECIST 1.1 (phase Ib and phase II part 2)   
• 
Progression Free Survival (PFS, phase Ib and phase II part 1)  
• 
Overall Survival (OS) 
• 
Duration of Response (DoR) 
• 
Disease control rate (DCR) 
• 
Safety profile (phase II) 
• 
Percentage of patients with liver metastases at baseline who have disease progression at D43 
(phase II part 2) 
 
Exploratory objectives 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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• 
 
 
 
 
 
 
  
Methodology 
This is a multicenter, open label phase Ib/II study evaluating the combination of TG4001 and avelumab 
in patients with HPV-16 positive advanced malignancies. 
The phase II consists of two parts: phase II part 1 is a single arm study (TG4001 with avelumab) and 
phase II part 2 is a randomized, controlled two arms study (TG4001 with avelumab vs avelumab alone). 
 
In the phase Ib: safety will be assessed in consecutive cohorts of 3 to 6 patients at increasing doses of 
TG4001 in combination with avelumab according to a 3+3 design (See Table below). There will be no 
intra-patient dose escalation. 
Patients will receive TG4001 on a weekly basis on Days 1, 8, 15, 22, and 29, then once every 2 weeks 
(starting on Day 36) until Month 6 (from Day 1 of study treatment), thereafter once every 12 weeks, 
until disease progression, unacceptable toxicity, patient withdrawal from study for any reason or for a 
maximum of 2 years, whichever occurs first. Avelumab will be given once every 2 weeks starting from 
Day 8 (one week after the first vaccine dose), until disease progression, unacceptable toxicity, patient 
withdrawal from study for any reason or for a maximum of 2 years, whichever occurs first. 
Beyond 2 years of treatment and based on the clinical judgement of the investigator the patient could 
continue to receive study treatments according to the Study Flow-Chart (APPENDIX IIIB). 
Dose escalation (3+3 design) 
Two dose levels are planned for TG4001: doses of 5 x 106 PFU (DL1) and 5 x 107 PFU (DL2) in 
combination with avelumab at 10 mg/kg. Depending on the nature of the dose limiting toxicity (DLT) 
observed at these two DLs, alternative schedule for TG4001 (Q4W) may be tested with the 
combination. In that case, a minimum of 6 additional patients will be included. Implementation of this 
alternative schedule will be subject to a substantial amendment to this clinical study protocol. 
Dose level 
TG4001 dose 
Avelumab dose  
Number of patients 
DL1 
5 x 106 PFU  
10 mg/kg  
3 – 6 
DL2 
5 x 107 PFU 
10 mg/kg 
3 – 6 
A minimum of 3 patients will be required at each dose level. If the maximum tolerated dose (MTD) is 
reached where 1 of 3 patients experiences a DLT, the cohort will be expanded with 3 additional patients 
at the same DL (a maximum of 6 patients will be enrolled at each DL). 
Enrolment within a given cohort: The first patient will be monitored for 2 weeks (i.e. 7 days after the 
first administration of both products in combination) before the next 2 patients of the cohort can be 
enrolled simultaneously. In case the cohort must be extended by 3 additional patients for occurrence of 
a DLT among the first 3 treated patients, an interval of 2 weeks will be applied between the first 
additional patient and the 2 additional next patients.  
Dose escalation rules and definition of MTD: 
All patients in a given DL must complete the first 4 weeks treatment from [Day 1 to Day 28] before 
dose escalation to the next dose level will occur.  
Patients who experience a DLT will be withdrawn from the study treatment and will not be replaced. 
Patients who are not evaluable for DLT or who are withdrawn from the study during the first 4 weeks 
of study treatment for other reasons than a DLT, will be replaced. Doses are escalated until MTD is 
reached as follows. 
Number of DLTs / evaluable 
patients  
Rule 
0/3 
Accrue 3 new patients at the next dose level 
1/3 
≥ 2/3 
Accrue 3 additional patients at current dose level 
Stop current dose = unacceptable dose 

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1/6 
MTD = dose immediately below 
Accrue 3 new patients at the next dose level 
≥ 2/6 
Stop current dose = unacceptable dose 
MTD = dose immediately below 
The dose level at which unacceptable toxicity in at least 2/3 or 2/6 patients occurs will be considered 
as the unacceptable dose. The MTD will be considered as the dose immediately below. If no DLT in 
more than 1/3 or 1/6 is observed, the MTD will be considered as the recommended dose for the phase 
II (RP2D).  
A total of 6 patients will be treated at the MTD. 
If at both Dose Levels no DLT in more than 1/3 or 1/6 patients is observed, the MAD, Maximum 
Administered Dose (DL2), will be considered as the recommended dose for the phase II (RP2D). 
Upon completion of phase Ib and for the purpose of clarification RP2D for TG4001 corresponds 
to DL2, i.e. 5 x 107 PFU. 
Dose limiting toxicity (DLT) will be assessed in each included and treated patient during the first 4 
weeks [Day 1 to Day 28] of dosing (4 injections of TG4001 and 2 injections of avelumab) and includes 
the following toxicities: 
• 
Grade ≥ 3 drug related adverse event (AEs). However, fatigue, nausea/vomiting adequately 
treated with anti-emetics, endocrinopathies adequately controlled with one physiologic 
hormone replacement, skin toxicity and single laboratory values out of normal range without 
any clinical correlate, asymptomatic grade ≥3 lipase or amylase elevation, tumor flare defined 
as local pain, irritation, or rash localized at sites of known or suspected tumor or a transient 
Grade 3 infusion adverse event are excluded. 
• 
Liver function test abnormality:  
o AST or ALT > 5 x ULN 
o Total bilirubin > 3 x ULN 
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• 
Drug related AE requiring treatment interruption for more than 2 weeks 
Toxicities will be graded according to National Cancer Institute’s Common Toxicity Criteria for 
Adverse Events (NCI-CTCAE), version 4.03. 
An Independent Data Monitoring Committee (IDMC) will be set up during the study for the purpose 
of reviewing patient safety data, efficacy data and the conduct of the study. 
During the phase Ib of the study, the safety data of all enrolled and treated patients will be collected 
and evaluated by the Investigators, Transgene and Merck KGaA / EMD Serono on an ongoing basis. 
The IDMC will meet before each new cohort begins to analyse and review the safety data of all patients 
in the previous cohort. The IDMC will then recommend whether it is possible to do the dose escalation 
as per the study design. 
At the end of the phase Ib and depending on the nature of the toxicities, the safety data of all patients 
will be analyzed and discussed with the IDMC which will make recommendation to the sponsor on the 
conduct of the study. DLT evaluation is performed 4 weeks after the last patient enrolled in the phase 
Ib had first dose of study treatments. 
During the phase II part 1 of the study the IDMC will review safety data at interim analysis. Ad hoc 
meetings may be held upon necessity.  
During the phase II part 2 of the study and in addition to safety review the IDMC will evaluate efficacy 
results at interim analysis.  
 
In the phase II part 1 patients will be treated at the established RP2D for TG4001, i.e. 5 x 107 PFU in 
combination with avelumab until disease progression, death, or unacceptable toxicity, or study 
withdrawal for any reason, or for a maximum of 2 years, whichever occurs first. 
In the phase II part 2 patients will be treated at the established RP2D for TG4001, i.e. 5 x 107 PFU in 
combination with avelumab 800 mg Q2W (combination arm) or with avelumab 800 mg Q2W alone 

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(monotreatment arm) until disease progression, death, or unacceptable toxicity, or study withdrawal for 
any reason, or for a maximum of 2 years, whichever occurs first. 
Beyond 2 years of treatment and based on the clinical judgement of the investigator the patient could 
continue to receive study treatments according to the Study Flow-Chart (APPENDIX IIIB and D). 
 
In the phase II part 1, evaluation of efficacy and further evaluation of safety of the combination of 
TG4001 and avelumab will be performed in a single arm of patients with recurrent or metastatic HPV-
16 positive advanced malignancies including HPV-16 positive oropharyngeal SCCHN.  
 
In the phase II part 2, evaluation of efficacy of the combination of TG4001 and avelumab will be 
performed in a randomized, open-label controlled study comparing TG4001 in combination with 
avelumab (combination arm) to avelumab alone (monotreatment arm) in patients with selected HPV-
16 positive recurrent or metastatic malignancies.  
In patients without liver metastases at baseline, randomization will be conducted equally in a 1:1 ratio 
TG4001 with avelumab (combination arm) versus avelumab alone (monotreatment arm). A 
stratification will be done on primary tumor site.  
In patients with liver metastases at baseline, randomization will be conducted equally in a 1:1 ratio 
TG4001 with avelumab versus avelumab alone, no stratification will be performed.   
 
In both phases tumor response will be evaluated at baseline and then every 6 weeks until disease 
progression. Beyond 9 months after start of treatment, tumor evaluation will be performed every 12 
weeks until disease progression.  
Tumor evaluations will be based on local assessment using RECIST 1.1. 
All patients will be followed up until disease progression or death due to any cause or the date of data 
cut-off, whichever occurs first. 
 
Number of Patients 
Phase Ib: a maximum of 12 evaluable patients depending on the safety of the combination 
Phase II part 1: at least 22 evaluable patients until the first stage of the Simon design 
Phase II part 2:  
• 
For patients without liver metastases a sample size of 50 patients (25 patients in each arm) is 
estimated to reach the number of PFS events required for Interim Analysis. PFS analysis is 
performed when 37 PFS events have been observed. 
 
 
 
 
 
 
• 
For patients with liver metastases at baseline a sample size of
 
is planned. 
Inclusion criteria 
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 (for phase II part 2: part 
of normal patient care can be: e.g. CT or MRI, biopsy, determination of HPV-16 positivity by 
specified central laboratory) 
2. Female or male patients, aged at least 18 years (no upper limit of age for phase Ib and phase II 
part 1), 18 to 80 years of age (for phase II part 2)  
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 (Appendix I) 
4. Life expectancy of at least 3 months 
5. Patients with histologically or cytologically documented metastatic or refractory/recurrent HPV-
16+ cancer (determined in an accredited central laboratory using a validated assay) 
6. Phase Ib and Phase II part 1: Patients with HPV-16+ cancers including oropharyngeal squamous 
cell carcinoma of the head and neck (SCCHN), cervical, vulvar, vaginal, penile, and anal cancer 

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Phase II part 2: Patients with HPV-16+ cancers including cervical, vulvar, vaginal, penile, and 
anal cancer 
7. Disease MUST not be amenable to curative surgery resection or curative radiotherapy with 
documented disease progression after concertation with multidisciplinary board  
8. Prior therapy 
Phase Ib and Phase II part 1: 
- Patients MAY have received up to two prior lines of systemic chemotherapy for the management 
of metastatic or recurrent disease; for SCCHN, patients MUST have previously been exposed to 
platinum-based therapy, either as part of definitive chemo-radiation OR as first line systemic 
treatment 
for 
metastatic 
disease 
which 
may 
include 
cetuximab. 
Patients 
with 
recurrence/progression within 6 months of prior multimodal therapy using platinum-based therapy 
are eligible. Patients with cervical cancer may have undergone surgery and/or received definitive 
radiation or chemo-radiation therapy for localized disease. Patients MUST have been exposed to 
platinum–based chemotherapy for metastatic disease which may include bevacizumab. Patients 
with platinum-refractory disease will be eligible 
Phase II part 2: 
- For recurrent/metastatic disease no more than one prior line of chemotherapy which can contain 
a platinum  
- Prior treatment for recurrent or metastatic disease is not required for:  
o Patients with recurrence/progression within 6 months after completion of prior 
multimodal therapy for localized or locally advanced disease not amenable to curative 
treatment  
o Patients who are unsuitable for platinum-based therapy  
o Patients who refuse chemotherapy or other standard therapies for the treatment of  
metastatic or recurrent disease. The benefit of an immunotherapy over standard 
therapies must be validated by the medical board and duly documented. 
A minimum of 4 weeks interval should have elapsed between the completion of the last 
chemotherapy and study treatment start 
A minimum of 4 weeks interval between palliative bone directed radiotherapy and the start of the 
study treatment provided that radiation therapy does not affect the unique measurable lesion, if 
applicable 
9. Phase II part 2: For patients with hepatic metastases  
- no more than 3 hepatic lesions in total (target and non-target lesions) 
- maximum size of hepatic target disease ≤ 30 mm according to RECIST 1.1 
10. Phase Ib and Phase II part 1: Availability of tumor tissue from biopsy: at least 2 fresh tumor 
tissue samples are to be collected. Tumor tissue may come either from the local tumor or distant 
metastasis. Cytological material is not accepted  
Phase II part 2: 
- Availability of archived or fresh tumor tissue for the determination of HPV-16 positivity.  
Patients must agree to undergo a core or excisional biopsy of a tumor lesion not previously 
irradiated (at least 2 fresh tissue samples to be collected). An archival sample obtained within one 
year prior to randomization is acceptable only if tumor is not accessible. Tumor tissue may come 
either from the local tumor or distant metastasis. Fine needle aspirates and bone biopsies are not 
adequate. 
11. At least one measurable lesion by CT scan according to RECIST 1.1. Tumors within a previously 
irradiated field will be designated as "non-target" lesions unless progression is documented or a 
biopsy is obtained to confirm persistence at least 90 days following completion of radiation 
therapy 
12. Adequate hematological, hepatic and renal function: 
- Hemoglobin  9.0 g/dL (for phase II part 2: without packed red blood cell transfusion within 
the prior 3 weeks) 
- Neutrophils  1.5x109/L 
- Total lymphocytes count  0.4x109/L 

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- CD4 + ≥ 200 / µL 
- Platelets count  100x109/L 
- Total bilirubin ≤ 1.5 x ULN 
- Serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) 
 3 x ULN  
- Glomerular Filtration Rate  50 mL/min (according to Modification of the Diet in Renal 
Disease (MDRD) formula or Cockroft & Gault formula) 
- Serum albumin ≥ 30 g/L 
13. Negative blood pregnancy test at screening for women of childbearing potential (Appendix II) 
14. Highly effective contraception (i.e., methods with a failure rate of less than 1% per year) during 
the study period and for 3 months after the last study treatment administration for female patients 
of childbearing potential (WOCBP) and for male patients who are sexually active with WOCBP 
(See Appendix II for WOCBP definition and details on highly effective contraception methods). 
Highly effective contraception methods are defined as: 
• 
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, intrauterine devices (IUDs) such as Mirena and Nonhormonal 
IUDs such as ParaGard for WOCBP patient or male patient’s WOCBP partner  
• 
Tubal ligation  
• 
Vasectomy 
In addition to highly effective contraception, participating male patients  
• 
must use a condom during the study period and for 3 months after the last study treatment 
administration when engaging in any activity that allows for exposure to ejaculate 
• 
must refrain from donating sperm 
 
Exclusion criteria 
1. Prior exposure to cancer immunotherapy including cancer vaccines, any antibody/drug targeting 
T cell co-regulatory proteins (immune checkpoints) such as anti-PD-L1, anti-PD-1, or anti-
cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody 
2. a) Concurrent anticancer treatment within 28 days before the start of study treatment (e.g., 
chemotherapy, radiotherapy or cytokine therapy except erythropoietin) 
b) Recurrent drainage procedures (once monthly or more frequently) for pleural effusion, 
pericardial effusion, or ascites  
3. Major surgery within 28 days before the start of study treatment  
4. 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 the first 
study treatment, 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 
5. Patients with central nervous system (CNS) metastases except those meeting the following 
criteria: 
- Brain metastases that have been treated locally and are clinically stable during 4 weeks prior 
to start of study treatment 
- No ongoing neurological symptoms that are related to the brain localization of the disease 
(sequelae that are a consequence of the treatment of the brain metastases are acceptable) 
6. Other active malignancy requiring concurrent systemic intervention 
7. Patients with previous malignancies other than the target malignancy to be investigated in this 
trial (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, 
endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission 
was achieved at least 2 years prior to study entry AND no additional therapy is required during 
the study period 
8. Patient with any organ transplantation, including allogeneic stem cell transplantation 
9. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTC V4.03 
or V5.0 for phase II part 2), any history of anaphylaxis, or uncontrolled asthma 

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10. Any known allergy or reaction to eggs, gentamycin or attributed to compounds of similar 
chemical or biological composition to therapeutic vaccines/immunotherapeutic products 
11. Any known allergy or reaction to any component of anti-PD-L1/PD-1 or its excipients  
12. Patients with history of interstitial lung disease (phase Ib and phase II part 1) 
13. Patients with known history or any evidence of active interstitial lung disease / pneumonitis (phase 
II part 2) 
14. Administration of a live vaccine within 28 days prior to the start of the study treatment 
15. Participation in a clinical study with an investigational product within 4 weeks prior to the start 
of the study treatment 
16. Patients with active, known, or suspected auto-immune disease or immunodeficiency, except type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement or skin disorders (such 
as vitiligo, psoriasis) not requiring systemic treatment  
17. Significant chronic or acute infections including infection with mpox and SARS-CoV-2 (COVID-
19) PCR positive testing 
18. Positive serology for Human Immunodeficiency Virus (HIV) or Hepatitis C Virus (HCV) or 
presence in the serum of the Hepatitis B surface antigens (HBsAg), at Baseline 
19. Persisting toxicity related to prior therapy of Grade ≥ 2 NCI-CTCAE v4.03 or v5.0 for phase II 
part 2 (except neuropathy [see exclusion criterion below] and alopecia) 
20. Neuropathy ≥ Grade 3 
21. Clinically significant (that is, active) cardiovascular disease: cerebral vascular accident/stroke or 
myocardial infarction (< 6 months prior to enrollment), unstable angina pectoris, congestive heart 
failure (New York Heart Association Classification Class ≥ II), or serious uncontrolled cardiac 
arrhythmia requiring medication/active intervention, history of myocarditis (history of 
myocarditis for phase II part 2)  
22. Patient with any underlying medical condition that the treating physician considers might be 
aggravated by treatment or might impair the patient’s tolerance to study treatment  
23. History of uncontrolled intercurrent illness including but not limited to: 
- Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mmHg or lower) 
- Uncontrolled diabetes (e.g., hemoglobin A1c ≥ 8%) 
- Uncontrolled infection (phase II part 2) 
24. Patients with pulse oximetry of less than 92% on room air (phase II part 2) 
25. Any psychological, familiar, sociological or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule; those conditions should be discussed 
with the patient before registration in the trial 
26. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 
10 mIU/mL) 
 Dose, Mode of Administration 
TG4001 
• 
TG4001 is an HPV-16 targeted immunotherapy derived from a replication deficient strain of 
vaccinia virus (Modified Vaccinia virus Ankara, MVA), engineered to express modified forms of 
the HPV-16 early proteins, E6 (delE6) and E7 (delE7), as well as the full length sequence of 
human interleukin 2 (IL-2). TG4001 is a suspension of recombinant viral particles suspended in 
a formulation medium. The formulation medium is also used as diluent for reconstitution to obtain 
the dose of 5 x 106 PFU (DL1). The product code of the diluent is TG0008. 
• 
TG4001 is supplied in 4-mL glass vials as a single dose for injection. The infectious titer of the 
active ingredient in the vial is 5 x 107 PFU in a recoverable volume of suspension of 0.5 mL. It 
will be administered as subcutaneous (SC) injections. TG0008 is supplied in 4-mL glass vials 
with a recoverable volume of solution in each vial of 0.5 mL. 
• 
Phase Ib, Phase II part 1 and Phase II part 2 combination arm: Patients will receive SC injections 
of TG4001 weekly on Days 1, 8, 15, 22, and 29, then once every 2 weeks (starting on Day 36)  
until Month 6 (Day 204), thereafter once every 12 weeks for a maximum of 2 years or until disease 

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progression or unacceptable toxicity, or premature discontinuation due to any reason, whichever 
occurs first. 
Avelumab  
• 
Avelumab is a fully human programmed death ligand 1 (PD-L1) blocking antibody. 
• 
Avelumab is supplied in a single-use type I glass vial for injection, containing 200 mg of the 
product at a concentration of 20 mg/mL. 
• 
Phase Ib and Phase II part 1: It will be administered as an IV infusion over 60 minutes at a dose 
of 10 mg/kg, starting one week (Day 8) after the first injection of TG4001, then once every 2 
weeks for a maximum of 2 years or until disease progression or unacceptable toxicity, or 
premature discontinuation due to any reason, whichever occurs first. The dose of avelumab will 
be calculated based on the weight of the subject determined within 72 hours prior to 
administration. The dose of avelumab used for the previous administration can be repeated if the 
change in the subject’s weight is 10% or less than the weight used for the last dose calculation. 
• 
Phase II part 2, both arms: It will be administered as an IV infusion over 60 minutes at a dose of 
800 mg, starting on Day 8, then once every 2 weeks for a maximum of 2 years or until disease 
progression or unacceptable toxicity, or premature discontinuation due to any reason, whichever 
occurs first. 
• 
For phase Ib and phase II part 1: In order to mitigate infusion-related reactions (IRRs), patients 
will 
receive 
pretreatment 
with 
histamine 
H1 
receptor 
(H1) 
blockers 
and 
acetaminophen/paracetamol 30 to 60 minutes prior to every avelumab infusion. A premedication 
regimen of 25 to 50 mg diphenhydramine and 500 to 650 mg acetaminophen/paracetamol (IV or 
oral equivalent) is recommended prior to each dose of trial drug. This regimen may be modified 
based on local treatment standards and guidelines as appropriate. 
• 
For phase II part 2: In order to mitigate IRRs, patients have to be premedicated with an 
antihistamine and with paracetamol (acetaminophen) prior to the first 4 infusions of avelumab. 
Premedication should be administered for subsequent avelumab doses based upon clinical 
judgement and presence/severity of prior infusion reactions. 
• 
When both drugs are given on the same day, premedication for avelumab and avelumab should 
be administered after TG4001 (Phase Ib, phase II part 1 and phase II part 2 for the combination 
arm). 
There will be no dose delay or dose reduction for TG4001 and avelumab in this study.  
If an AE is related to only one agent (TG4001 or avelumab) and dose omission is required, the other 
agent continues as planned (Phase Ib, phase II part 1 and phase II part 2 for the combination arm).  
Beyond 2 years of treatment and based on the clinical judgement of the investigator the patient could 
continue to receive study treatments according to the Study Flow-Chart (APPENDIX IIIB and D). 
 
Reference / Associated Therapy 
Permitted medicines and therapies: 
• 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. 
• 
The use of the following drugs will not be restricted during the course of the study: erythropoietin, 
antiemetics, amifostine, folates, vitamin B12 and vitamin D. 
• 
The use of systemic corticosteroids during the study is restricted as follows: for short term treatment 
(≤7 days) of allergic reactions or for the treatment of irAEs, or for replacement for adrenal 
insufficiency at doses equivalent to ≤ 10 mg prednisone daily. 
• 
Radiotherapy for pain relief (e.g., bone metastases) is permitted. If lesions are in the field of 
radiation they will be no longer evaluable for the tumor response, patients receiving palliative 
radiotherapy will be analyzed separately.  
Non permitted medicines and therapies during the study treatment: 
• 
Any live vaccine for the prevention of infectious disease (e.g., human papilloma virus vaccine). 

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• 
Growth factors (granulocyte colony stimulating factor or granulocyte macrophage colony 
stimulating factor), except erythropoietin and darbepoietin alpha (may be prescribed at the 
investigator’s discretion). 
• 
Bisphosphonate or denosumab treatment is not allowed unless it has been initiated more than 14 
days prior to receiving the first administration of study treatment. 
Duration of Study Treatment  
The study treatments will be administered until disease progression, or unacceptable toxicity, or patient 
withdrawal for any reason or for a maximum of 2 years, whichever occurs first. 
Beyond 2 years of treatment and based on the clinical judgement of the investigator the patient could 
continue to receive study treatments according to the Study Flow-Chart (APPENDIX IIIB and D). 
Depending on the response, the following rules will be applied: 
• 
Patients who achieve a confirmed complete response (CR) MAY stop the treatment earlier at the 
discretion of the investigator provided that they have been treated for a minimum of 12 months. 
After discontinuation of the study treatment, patients will be followed until disease progression or 
death due to any cause or the date of data cut-off, whichever occurs first. 
• 
Patients with a response of partial response (PR) / stable disease (SD) will continue to receive 
TG4001 and avelumab until achievement of a confirmed CR, disease progression, development of 
unacceptable toxicity or until they have received a maximum of 2 years of study treatment, 
whichever occurs first. Beyond 2 years of treatment and based on the clinical judgement of the 
investigator the patient could continue to receive study treatments according to the Study Flow-
Chart (APPENDIX IIIB and D). 
• 
Patients with progressive disease (PD) based on RECIST 1.1 will stop study treatment and complete 
the off-treatment procedures in phase I and phase II part 1.  
• 
In phase II part 2 at the 1st radiologic evidence of PD, clinically stable patients may continue study 
treatment at the Investigator’s discretion while awaiting a confirmatory scan. If repeat imaging 
confirms PD, study treatment must be discontinued except if the patient is clinically stable or 
clinically improved, and there is no further increase in the target lesions, no unequivocal increase 
in non-target lesions, and no additional new lesions (non-worsening PD). If repeat scan shows SD, 
PR or CR patient continues study treatment and imaging assessment should be performed every 6 
weeks.  
• 
Patients who are withdrawn from study drug treatment for reasons other than disease progression 
will be followed until disease progression or death due to any cause or the date of data cut-off 
whichever occurs first.  
Criteria for Evaluation / Endpoints 
Safety assessment 
• 
Physical examination including vital signs and body weight will be performed at each visit. 
Performance Status will be recorded every 2 weeks.  
• 
AEs and Serious Adverse Events (SAEs) will be reported and graded according to NCI CTCAE, 
version 4.03 for phase Ib and phase II part 1 or version 5.0 for phase II part 2 at each visit, at the 
end of treatment visit and at the safety follow-up visit. 
• 
Laboratory investigations will be undertaken: 
- 
Complete blood cells count at baseline, on Days 1 (phase Ib and phase II part 1 only), 8, 15, 
22, 29 and 36, then every 2 weeks up to Month 6 (D204), thereafter every 6 weeks, at the end 
of treatment visit and at the safety follow-up visit 
- 
Biochemistry analyses (including: AST, ALT, alkaline phosphatases, total bilirubin, lipase, 
amylase, LDH, serum protein, serum albumin, glucose, electrolytes) and creatinine, at baseline, 
on Days 1 (phase Ib and phase II part 1 only), 8, 15, 22, 29 and 36, then every 2 weeks up to 
Month 6 (D204), thereafter every 6 weeks, at the end of treatment visit and at the safety follow-
up visit 
- 
TSH will be performed at baseline, on Day 36, then every 6 weeks and at the end of treatment 
visit 
- 
Free T4 will be performed at baseline and at the end of treatment visit 

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- 
Blood pregnancy test at baseline, on Day 36, then every 6 weeks, at the end of treatment visit 
and the safety follow-up visit for women of childbearing potential  
• 
Electrocardiogram (12 leads) will be performed: 
- 
 At baseline and at the end of treatment visit 
- 
During treatment period as clinically indicated: In case of potential symptoms of myocarditis / 
pericarditis during study treatment (such as chest pain, shortness of breath, heart palpitations, 
and reduced tolerance to exercise), cardiac laboratory analyses (e.g. creatinine kinase-
myocardial band, troponin), ECG and echocardiography (or MUGA scan) will be requested. If 
abnormal findings indicate possible myo- or pericarditis, the patient will be referred to 
consulting a cardiologist. 
Efficacy assessment will be based on local evaluations using RECIST 1.1. 
• 
Patients will have at least one measurable lesion by CT/MRI scan (minimum size not less than 
10 mm). All target lesions (measurable) and non-target lesions (measurable or not) will have to be 
recorded. Preferably CT (or MRI) of the head and neck, chest, abdomen and all other known sites 
of disease (e.g. pelvis, if applicable) will be performed within 21 days prior to start of study 
treatment. Patients will be evaluated every 6 weeks from start of treatment until disease progression 
or for a period of 9 months after start of study treatment, whichever occurs first. Beyond 9 months 
of treatment, the evaluations will be performed every 12 weeks until disease progression.  
• 
Overall Response Rate (ORR): proportion of patients with CR or PR. 
• 
Disease Control Rate (DCR): proportion of patients with CR, PR or SD. 
• 
Duration of overall Response (DoR): applies only to patients with CR or PR. The start date is the 
date of first documented response (CR or PR) and the end date is the date of first documented 
disease progression or the date of death due to underlying cancer. 
• 
Progression Free Survival (PFS):  
Phase Ib and phase II part 1: time from the date of first study treatment administration to the date 
of first documented tumor progression or death due to any cause, whichever occurs first. 
Phase II part 2: time from the date of randomization to the date of first documented disease 
progression or death due to any cause, whichever occurs first. 
• 
Overall Survival (OS):  
Phase Ib and phase II part 1: time from date of first study treatment administration to the date of 
death due to any cause. If a patient is not known to have died at the cut-off date for analysis, survival 
will be censored at the date of last contact. 
Phase II part 2: time from the date of randomization to the date of death due to any cause. If a 
patient is not known to have died at the cut-off date for analysis, survival will be censored at the 
date of last contact. 
PFS and OS will be calculated using the Kaplan-Meier method.  
Immunology and translational research  
Blood and tumor samples collection: 
• 
Blood: 
- 
For phase Ib and phase II part 1: blood samples (prior to drug administration, when applicable) 
at Baseline, on Day 1, Day 8 (except for PBMC), Day 43, Day 85 (except for PBMC), Month 
6, Month 12 and Month 24. 
- 
For phase II part 2: blood samples (prior to drug administration, when applicable) at Baseline, 
on Day 1, Day 8 (except for PBMC), Day 15, Day 43, Day 85, Month 6 (D204), Month 9 
(D288), and Month 12 (D372, except for PBMC). Furthermore, on D1 6 hours post-dose 
(except for PBMC) for patients randomized in the combination arm and treated with TG4001.  
• 
Tumor 
- 
For phase Ib and phase II part 1: tumor biopsies at baseline, on Day 43 and Day 85 (unless it 
is unsafe or undesirable) 
- 
For phase II part 2: in patients with accessible lesions tumor biopsies at baseline, in patients 
with accessible lesions and under study treatment on Day 85 and at Month 9 (D288). In patients 
with accessible lesions at time of progressive disease. 

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Blood samples will be collected to assess the following parameters: 
• 
 
 
 
 
 
  
 
 
 
Tumor sample(s) will be collected to assess: 
• 
 
  
 
  
 
  
 
 
 
  
Statistical Methods: 
Populations of analyses and statistical analysis 
Safety population (SAF): all patients included and who received any amount of study treatment will be 
included in the SAF. Any patient who is assigned a patient number, but does not receive any study 
treatment will not be included in the SAF. 
Evaluable patients’ population for DLT determination (DLT population): For the phase Ib of the study, 
the purpose being to evaluate the safety of the combination, patients must complete the first 4 weeks of 
the combination or discontinue before the end of the 4 weeks for a DLT to be evaluable for the primary 
objective of the phase Ib of the study. Patients who are not evaluable for phase Ib safety analysis or are 
withdrawn for other reasons than toxicity, will be replaced.  
Patients must receive at least one dose of both IMPs (TG4001 + avelumab) and have at least one valid 
post-baseline safety assessment. The statement that a patient had no AE, on the Adverse Events eCRF 
page, constitutes a valid safety assessment. The occurrence of death also constitutes a valid safety 
assessment.  
Phase II part 1: Evaluable patients’ population for tumor response (evaluable per protocol population, 
EPP): consists of all included patients who were dosed with both IMPs (TG4001 + avelumab) and have 
at least one baseline and one post-baseline evaluable CT-scan at week 6 after start of study treatment 
with a best overall response assessment different from ‘Unknown’ according to RECIST 1.1 evaluation 
criteria. However, if a patient progressed or died due to underlying cancer before scheduled scan 6 
weeks after study treatment start could be performed, the patient will still be included in the evaluable 
population. Any patient who has a major inclusion/exclusion violation, major dosing violation, or major 
protocol conduct violation will be excluded from the EPP. Major dosing violation is considered when 
minimum exposure is not met, defined as at least 6 TG4001 injections and 3 avelumab administrations 
except if patient has progressed or died due to underlying disease before or at the first evaluation. Due 
to potential abscopal effect when associating radiotherapy and immunotherapy, patients receiving 
palliative radiotherapy will be analyzed separately. Whatever the reason for withdrawal, except for 
disease progression and death due to underlying cancer before scheduled scan 6 weeks after study 
treatment start could be performed, patients considered as non-evaluable for tumor response will be 
replaced. 
Descriptive statistics will be used. For all analyses, results and graphical representation of data will be 
presented by dose level and phase II cohort. 
No statistical analyses will be performed on safety data. Safety summary tables will include all safety 
assessments up to 90 days after last study treatment administration. 
 
Phase II part 2:  

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Full Analysis Set (FAS) will be the primary set for efficacy analyses. It consists of all randomized 
patients who were administered at least one dose of IMP(s) according to the treatment allocated at 
randomization.  
Evaluable patients’ population (evaluable per protocol population, EPP): consists of all patients from 
the FAS without any major inclusion/exclusion violation, major dosing violation as defined for phase 
II part 1, or major protocol conduct violation who were dosed with IMP(s) according to the treatment 
allocated at randomization and have at least one baseline and one post-baseline evaluable CT-scan at 
week 6 after start of study treatment with a best overall response assessment different from ‘Unknown’ 
according to RECIST 1.1 evaluation criteria.  
 
Sample size: 
Phase Ib of the study: there will be no formal sample size for the phase Ib of the study. The dose 
escalation part of the trial follows the methodology of a 3+3 cohort design for dose-finding studies in 
oncology. Depending on the observed DLTs, a maximum of 12 evaluable patients will be included in 
this part of the study. 
 
Phase II part 1: a Simon’s two-stage design will be used. The null hypothesis for response rate H0 is set 
at 10% corresponding to the response rate observed in second line patients, the alternative hypothesis 
of efficacy is set at HA=25%, the type I error α is set at 5% one sided, the type II error β is set at 20% 
(power=80%). Under these hypotheses and applying a minimax two-stage Simon design, enough 
patients will be treated to obtain 22 evaluable patients as a first stage. If at least 3/22 patients are 
considered responders, the enrolment will be continued, otherwise it will be stopped. In the initial 
design and at the second stage enough patients should have been treated to obtain at least 40 evaluable 
patients in total. The study would have been considered positive with at least 8/40 responders. With a 
hierarchical strategy on the final analysis, a subgroup analysis performed in oropharyngeal SCCHN 
patients and with a null hypothesis for response rate (H0) set at 10% and the alternative hypothesis of 
efficacy set at HA = 35%, 18 oropharyngeal SCCHN patients would have been needed to reach a power 
of 81% and actual alpha at 2.8%. This analysis would have been considered positive with at least 5 
responders among the 18 SCCHN patients. The second stage of the Simon’s design has not been done 
following the decision to exclude oropharyngeal SCCHN and to change to a randomized controlled 
two-arms study (phase II part 2).  
 
Phase II part 2:  
• 
For the cohort of patients without liver metastases at baseline, an adaptive sample size re-
estimation is applied: based on the results obtained in phase II part 1, the hypothesis for median 
PFS in the combination arm (TG4001 with avelumab) is set at 4.5 months. The hypothesis for 
median PFS in the monotreatment arm (avelumab alone) is set at 2 months. The type I error α 
is set at 5% one sided, the type II error β is set at 5%. 
A two-stage group sequential design will be used with logrank test and boundary for efficacy 
at alpha=0.00001 and Conditional Power (CP) at 10% for futility.  
 
At the interim analysis, a first test for efficacy is performed on 37 PFS events at a level of 
significance of 0.000001. A sample size of 50 patients is estimated at time of the Interim 
Analysis. 
Otherwise, the following decision rules are applied based on CP using CHW (Cui, Hung and 
Wang) approach. 
 
➢ Favorable zone: If the interim results are sufficiently favorable corresponding to a CP of more 
than 90%, final analysis will be performed on 74 PFS events corresponding to an estimated 
sample size of 80 patients.   
 
➢ Promising zone: If the interim results are equivalent to a CP between 90% and 30%, the sample 
size will be recalculated according to the median PFS observed in the two arms with a cap of 
2 times the initial number of events.  

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➢ Unfavorable zone: If the interim results are not favorable corresponding to a CP between 30% 
and 10%, the trial may continue up to the initial sample size of 80 patients or could be stopped. 
 
➢ Futility zone: If the interim results are futile corresponding to a CP lower than 10%, the trial 
will be stopped for futility at the interim analysis. 
 
Assuming uniform enrollment with 3 patients per month, an average of 136 patients are needed to 
observe 124 PFS events. Assuming a 5% lost to follow-up or withdrawal of consent rate, a total of 
142 patients should be randomized to the 2 treatment arms in a 1:1 ratio (71 patients in each 
treatment arm). 
 
 
 
 
 
 
 
 
 
• 
For the cohort of patients with liver metastases at baseline, 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
INVESTIGATORS / STUDY ADMINISTRATIVE STRUCTURE .................................................................. 2 
DOCUMENT APPROVAL ................................................................................................................................... 3 
SYNOPSIS .............................................................................................................................................................. 4 
TABLE OF CONTENTS ..................................................................................................................................... 17 
ABBREVIATIONS / DEFINITION OF TERMS ............................................................................................. 21 
1 
INTRODUCTION .................................................................................................................................. 26 
 
BACKGROUND AND INTRODUCTION ..................................................................................................... 26 
 
Human PapillomaVirus (HPV) and related diseases ..................................................................... 26 
 
Role of HPV in the carcinogenesis of SCCHN ............................................................................... 27 
 
HPV vaccine ................................................................................................................................... 27 
 
PD-1 and PD-L1 pathway and immune responses ......................................................................... 28 
 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) ............................................................................... 29 
 
TG4001 ........................................................................................................................................... 29 
 
Avelumab ........................................................................................................................................ 32 
 
RATIONALE FOR CONDUCTING THE TRIAL ............................................................................................ 42 
 
Rationale for selecting SCCHN in the phase II of the study........................................................... 42 
 
Rationale for the use of checkpoint inhibitors in HPV-positive SCCHN ....................................... 43 
 
Rationale for the use of cancer vaccines in SCCHN ...................................................................... 45 
 
Rationale for combining TG4001 and immune checkpoints inhibitors .......................................... 46 
 
Rationale for including other HPV-16 positive malignancies in the phase II of the study ............. 46 
 
Rationale for the exclusion of oropharyngeal SCCHN in phase II part 2 ...................................... 46 
 
Rationale for transforming the phase II into a randomized, open-label controlled study .............. 47 
 
Rationale for the restriction on the extent of liver metastases for eligibility in phase II part 2 ..... 48 
 
SUMMARY OF THE OVERALL BENEFIT AND RISK................................................................................... 48 
 
Expected benefits ............................................................................................................................ 48 
 
Potential risks................................................................................................................................. 49 
 
Measures taken during the study to mitigate the risks ................................................................... 50 
2 
OBJECTIVES ........................................................................................................................................ 50 
 
PRIMARY OBJECTIVE ............................................................................................................................ 50 
 
SECONDARY OBJECTIVES (PHASE IB + II) ............................................................................................ 50 
 
EXPLORATORY OBJECTIVES (PHASE IB +II) .......................................................................................... 51 
3 
STUDY DESIGN .................................................................................................................................... 51 
 
OVERALL STUDY DESIGN AND PLAN DESCRIPTION ............................................................................... 51 
 
Overall design and treatment plan ................................................................................................. 51 
 
Number of centers and patients ...................................................................................................... 56 
 
Independent Data Monitoring Committee ...................................................................................... 56 
 
Patient accrual and duration of study ............................................................................................ 57 
 
DISCUSSION OF STUDY DESIGN ............................................................................................................ 57 
 
DOSES AND SCHEDULE SELECTION ....................................................................................................... 58 
 
TG4001 doses selection .................................................................................................................. 58 
 
TG4001 schedule selection ............................................................................................................. 58 
 
Avelumab dose selection ................................................................................................................ 59 
4 
STUDY POPULATION ........................................................................................................................ 60 
 
INCLUSION CRITERIA............................................................................................................................ 60 
 
EXCLUSION CRITERIA .......................................................................................................................... 62 
 
CRITERIA FOR PATIENT PREMATURE WITHDRAWAL AND REPLACEMENT .............................................. 64 
 
Premature withdrawal from the trial ............................................................................................. 64 
 
Withdrawal from the Investigational Medicinal Products ............................................................. 64 
 
Replacement policy ........................................................................................................................ 64 
 
DEFINITION OF END OF STUDY (EOS).................................................................................................. 65 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) .............................................................. 65 

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TG4001 ............................................................................................................................................... 65 
 
Packaging and labeling .................................................................................................................. 65 
 
Conditions of storage and use ........................................................................................................ 66 
 
Preparation for administration ...................................................................................................... 66 
 
Disposal and destruction or return ................................................................................................ 66 
 
Supplier .......................................................................................................................................... 67 
 
AVELUMAB .......................................................................................................................................... 67 
 
Packaging and labeling .................................................................................................................. 67 
 
Conditions of storage and use ........................................................................................................ 68 
 
Preparation for administration ...................................................................................................... 68 
 
Disposal and destruction or return ................................................................................................ 68 
 
Supplier .......................................................................................................................................... 69 
6 
TREATMENT PLAN ............................................................................................................................ 69 
 
TRIAL MEDICATION ADMINISTRATIONS................................................................................................ 69 
 
TG4001 ........................................................................................................................................... 69 
 
Avelumab ........................................................................................................................................ 71 
 
PLANNED STUDY TREATMENT DURATION AND OBSERVATION PERIOD ................................................. 72 
 
Planned duration of study treatment in case of related toxicity to one of the IMPs ....................... 73 
 
Planned duration of study treatment according to response .......................................................... 73 
 
CONCOMITANT THERAPIES AND MEDICATIONS .................................................................................... 74 
 
Concomitant medications ............................................................................................................... 74 
 
Permitted medicines and therapies ................................................................................................ 74 
 
Non-permitted medicines and therapies ......................................................................................... 74 
 
Considerations for Steroids use during the trial ............................................................................ 75 
 
Other trial considerations .............................................................................................................. 75 
 
Special precautions ........................................................................................................................ 75 
 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS ................................................................. 76 
 
Recruitment .................................................................................................................................... 76 
 
Randomization................................................................................................................................ 76 
 
DOSE MODIFICATIONS .......................................................................................................................... 76 
 
TG4001 ........................................................................................................................................... 77 
 
Avelumab ........................................................................................................................................ 77 
 
BLINDING / UNBLINDING ..................................................................................................................... 87 
 
TREATMENT COMPLIANCE ................................................................................................................... 87 
 
Dispensing and accountability ....................................................................................................... 87 
 
Assessment of compliance .............................................................................................................. 87 
 
END OF TREATMENT VISIT .................................................................................................................... 87 
 
MEDICAL CARE OF PATIENTS AFTER END OF STUDY ............................................................................. 88 
 
FOLLOW-UP FOR PFS AND SUBSEQUENT ANTINEOPLASTIC THERAPY................................................... 88 
 
SAFETY FOLLOW-UP VISIT .................................................................................................................... 88 
 
FOLLOW-UP FOR SURVIVAL AND SUBSEQUENT ANTINEOPLASTIC THERAPY ......................................... 88 
7 
STUDY VISITS AND PROCEDURES ................................................................................................ 88 
 
EVALUATIONS DESCRIPTION ................................................................................................................ 89 
 
BASELINE ............................................................................................................................................ 90 
 
DURING THE STUDY TREATMENT PERIOD ............................................................................................. 91 
 
END OF TREATMENT VISIT .................................................................................................................... 93 
 
SAFETY FOLLOW-UP VISIT .................................................................................................................... 93 
 
SAFETY FOLLOW-UP PHONE CALL ........................................................................................................ 93 
 
POST-STUDY FOLLOW-UP ..................................................................................................................... 94 
 
BIOMARKERS AND TRANSLATIONAL RESEARCH .................................................................................. 94 
 
Immunomonitoring ......................................................................................................................... 94 
 
Handling of biological and tissue samples ..................................................................................... 96 
8 
ASSESSMENT OF EFFICACY ........................................................................................................... 96 
9 
ASSESSMENT OF SAFETY ................................................................................................................ 97 
 
DEFINITIONS ........................................................................................................................................ 97 
 
TIME PERIOD FOR COLLECTION .......................................................................................................... 100 

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ADVERSE EVENT / SERIOUS ADVERSE EVENT MANAGEMENT ............................................................. 100 
 
Data collection ............................................................................................................................. 100 
 
Follow-up ..................................................................................................................................... 102 
 
Documentation ............................................................................................................................. 103 
 
REPORTING OF DLTS DURING THE PHASE IB OF THE STUDY............................................................... 103 
 
SERIOUS ADVERSE EVENT / SERIOUS ADVERSE REACTION / SUSPECTED UNEXPECTED SERIOUS 
ADVERSE REACTION NOTIFICATION .................................................................................................. 103 
 
SPECIAL SITUATIONS.......................................................................................................................... 104 
 
LABORATORY VALUES, VITAL SIGNS, PHYSICAL FINDINGS AND OTHER SAFETY DATA ....................... 105 
10 
STATISTICAL METHODS PLANNED AND SAMPLE SIZE ...................................................... 105 
 
DATA SETS ANALYZED ....................................................................................................................... 105 
 
DETERMINATION OF SAMPLE SIZE ...................................................................................................... 106 
 
STUDY ENDPOINTS ............................................................................................................................. 109 
 Primary endpoint ......................................................................................................................... 109 
 Secondary endpoints .................................................................................................................... 110 
 Exploratory endpoints (phase Ib and II) ...................................................................................... 111 
 
STATISTICAL AND ANALYTICAL PLANS .............................................................................................. 111 
 Safety analyses ............................................................................................................................. 111 
 Efficacy analyses .......................................................................................................................... 112 
 Biomarkers ................................................................................................................................... 114 
 
METHODS OF ANALYSIS ..................................................................................................................... 114 
 General considerations ................................................................................................................ 114 
 Disposition of patients .................................................................................................................. 114 
 Demographic and baseline characteristics .................................................................................. 115 
 Treatments .................................................................................................................................... 115 
 
PROTOCOL DEVIATIONS ..................................................................................................................... 116 
11 
CHANGES IN THE CONDUCT OF THE STUDY.......................................................................... 116 
 
PROTOCOL AMENDMENTS .................................................................................................................. 116 
 
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY ............................................................... 116 
12 
ETHICAL CONSIDERATIONS ........................................................................................................ 117 
 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD ................................................ 117 
 
INFORMED CONSENT .......................................................................................................................... 117 
 
CONFIDENTIALITY OF PATIENT DATA ................................................................................................. 118 
13 
REGULATORY CONSIDERATIONS .............................................................................................. 118 
 
REGULATORY CONSIDERATIONS ........................................................................................................ 118 
 
REGULATORY APPROVAL / AUTHORIZATION ...................................................................................... 118 
 
INVESTIGATORS’ OBLIGATIONS .......................................................................................................... 119 
 
INSURANCE ........................................................................................................................................ 119 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................. 119 
 
ON SITE  MONITORING ........................................................................................................................ 119 
 
AUDIT AND INSPECTION ..................................................................................................................... 120 
15 
DATA HANDLING AND RECORD KEEPING .............................................................................. 120 
 
SOURCE DATA AND DOCUMENTS........................................................................................................ 120 
 
CASE REPORT FORMS ......................................................................................................................... 121 
16 
CLINICAL STUDY REPORT AND PUBLICATION ..................................................................... 121 
 
CLINICAL STUDY REPORT ................................................................................................................... 121 
 
CONFIDENTIALITY OF STUDY DATA ................................................................................................... 121 
 
PUBLICATION POLICY ........................................................................................................................ 122 
17 
ARCHIVING ........................................................................................................................................ 122 
 
INVESTIGATOR SITE FILE .................................................................................................................... 122 
 
TRIAL MASTER FILE ........................................................................................................................... 122 

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18 
REFERENCES ..................................................................................................................................... 123 
19 
APPENDICES ...................................................................................................................................... 133 

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ABBREVIATIONS / DEFINITION OF TERMS 
ABBREVIATIONS 
MEANING OF ABBREVIATIONS IN DOCUMENT 
ADA 
Anti Drug Antibody 
ADCC 
Antibody Dependent–Cell mediated Cytotoxicity 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Alanine amino-transferase (= SGOT) 
ANA 
Anti-Nuclear Antibodies 
ANCA 
Antineutrophil cytoplasmic antibody 
AST 
Aspartate amino-transferase (= SGPT) 
C trough 
Concentration at the end of dose interval 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIN 
Cervical Intraepithelial neoplasia 
CNS 
Central Nervous System 
CP 
Conditional Power 
CR 
Complete Response 
CRA 
Cytokine Release Assays 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T Lympocytes 
CxCa 
Cervix cancer 
D 
Day 
DC 
Dendritic Cells 
DCR 
Disease Control Rate 
DL 
Dose Level 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic acid  
DoR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal Growth Factor Receptor 
EPP 
Evaluable per Protocol Population 
FACS 
Fluorescence-activated cell-sorting 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
GCP 
Good Clinical Practice 
GMO 
Genetically Modified Organism 
HBV 
Hepatitis B Virus 
hCG 
human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HLA 
Histocompatibility Leukocyte Antigen 
HNC 
Head and Neck Cancer 
HPV 
Human Papilloma Virus 
HR 
Hazard Ratio 
IB 
Investigator’s brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medicinal Journal Editors 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN 
Interferon 

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IL 
Interleukin 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IO 
Immuno-Oncology 
IRB 
Institutional Review Board 
IRR 
Infusion-Related Reaction 
irAE 
Immune-related Adverse Event 
ISH 
In Situ Hibridization 
IU 
International Unit 
IUD 
Intrauterine devices 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal 
M 
MAD 
Month 
Maximum Administered Dose 
MDRD 
Modification of the Diet in Renal Disease 
MoAb 
Monoclonal Antibody 
mL 
Milliliters 
MTD 
Maximum Tolerated Dose 
MRI 
Magnetic Resonance Imaging 
MVA 
Modified Vaccinia virus Ankara 
NCI-CTCAE 
National Cancer Institute’s Common Terminology Criteria for Adverse Events. 
Also referred as CTCAE in the text 
NK 
Natural Killer 
NOAEL 
No Observed Adverse Effect Level 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PD-1 
Programmed-Death 1 
PD-L1 
Programmed-Death Ligand 1 
PHA 
Phytohemaglutinin 
PFS 
Progression Free Survival 
PFU 
Plaque Forming Unit 
PR 
Partial Response 
PS 
Performance Status 
Q2W 
Every two Weeks 
Q4W 
Every four Weeks 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SC 
Subcutaneous 
SCCHN 
Sd 
Squamous Cell Carcinoma of Head and Neck 
standard deviation 
SD 
Stable Disease 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAA 
Tumor Associated Antigen 
TCR 
Tumor Cross reactivity 
TEAE 
Treatment Emergent Adverse Event 
TIL 
Tumor Infiltrating Lymphocytes 
TMF 
Trial Master File 
TPO 
Thyroid Peroxidase 
TO 
Target Occupancy 
ULN 
Upper Limit of Normal 

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VIN 
Vulvar Intraepithelial neoplasia 
WBC 
White Blood Cells 

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ABBREVIATIONS / DEFINITION OF TERMS (Cont.) 
 
 
DEFINITIONS 
 
Consented patient 
A patient who has signed the informed consent form. 
Screened patient 
A patient identified during the pre-screening process as a candidate 
for entry into the study and who has signed the Informed Consent 
Form (ICF) to undergo procedures required to verify the eligibility 
criteria before inclusion 
Screen Failure 
Any patient who underwent screening procedures, and who is found 
to be not eligible for entry into study and therefore does not receive 
any study treatment. 
Included patient 
A patient who signed the ICF, has been included in the study and 
has received at least one administration of study treatments (TG4001 
or avelumab). 
Lost of follow-up 
patient 
An included patient for whom no further news is obtained by the 
Investigator before the last study assessment. The date of lost of 
follow-up is the date the Investigator received the last news from the 
patient i.e. during a visit or a telephone contact or any written means. 
Protocol deviation 
All non adherences to following protocol requirements: study 
inclusion or exclusion criteria, conduct of the study, patient 
management or patient assessment. 
Evaluable patients 
Evaluable patients for DLT determination: patients must complete 
the first 4 weeks of the combination or discontinue before the end of 
the 4 weeks for a DLT. Patients must receive at least one dose of 
both IMPs (TG4001 + avelumab) and have at least one valid post-
baseline safety assessment.  
Patients who are not evaluable for phase Ib safety analysis or are 
withdrawn for other reasons than toxicity, will be replaced. 
 
Phase II part 1: Evaluable patients population for tumor response: 
patients who were dosed with both IMPs (TG4001 + avelumab) and 
have at least one baseline and one post-baseline evaluable CT-scan 
at week 6 after start of study treatment with a best overall response 
assessment different from ‘Unknown’ according to RECIST 1.1 
evaluation criteria and have no major protocol violations or major 
dosing violations.  Major dosing violation is considered when 
minimum exposure is not met, defined as at least 6 TG4001 
injections and 3 avelumab administrations except if patient has 
progressed or died due to underlying disease before or at the first 
evaluation. 
Phase II part 2: Full Analysis Set (FAS) which consists of all 
randomized patients who were administered at least one dose of 
IMP(s) according to the treatment allocated at randomization. 

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Start of study 
treatment 
Corresponds to date of Day 1 for phase Ib and phase II part 1 and to 
date of randomization for phase II part 2 

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1 INTRODUCTION 
 
 Background and introduction 
 
 Human PapillomaVirus (HPV) and related diseases 
 
Human papillomavirus (HPV) is the most common diagnosed sexually transmitted infection. It 
is associated with condyloma acuminata, anogenital (cervical, vaginal, vulval, penile, anal) 
squamous intraepithelial lesions and malignancies, and also squamous cell carcinoma of the 
head and neck (SCCHN). 
 
HPV is a small deoxyribonucleic acid (DNA) virus of approximately 7900 base pairs. The HPV 
genome encodes DNA sequences for six early (E) proteins associated with viral gene regulation 
and cell transformation, two late proteins which form the shell of the virus, and a region of 
regulatory DNA sequences known as the long control region or upstream regulatory region 
(Palefsky J.M. and Holly E.A., 1995). 
 
HPV genotypes can be broadly split into “high-risk” (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 
59 and 68) and “low-risk” (6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 73 and 81) based upon their 
malignant potential. Types 16 and 18 are the most commonly isolated HPV types in cancer with 
type 16 found in approximately 50 % of patients with cervical cancer for example (de Sanjose 
S. et al., 2010). However, not all infections with HPV type 16 or 18 progress to cancer. 
Furthermore, within single oncogenic HPV types, variants exist that are associated with 
different oncogenic potential (Hildesheim A. et al., 2001). Beyond causing cervical cancer, 
HPV is also implicated in cancer of the anus (Tilston P., 1997) and penis (Varma V.A. et al., 
1991). There is also an approximately 2 to 3 fold increased risk for cancers of the oral cavity 
and oropharynx in patients infected with high-risk (oncogenic) HPV subtypes: HPV-16 
genotype but also HPV-18, 31 or 33 (de Sanjose S. et al., 2010), (Hildesheim A. et al., 2001). 
HPV associated tumors predominantly arise in the base of the tongue or the tonsillar region, 
although a small percentage of tumors at other sites are also HPV positive. It is unclear why the 
oropharynx is more susceptible to HPV transformation than other sites.  
 
Cohort studies from the 1990s suggested that approximately 50 % of oropharyngeal cancers 
were attributable to HPV, while more recent studies suggest that HPV may account for as much 
as 70 to 80% of these malignancies (Sturgis E.M. and Ang K.K., 2011), (Chaturvedi A.K. et 
al., 2011). 
 
A review on the published clinical trials, both single-arm and randomized, demonstrated HPV 
positivity ranging from 20 to 60% of oropharyngeal cancers (Ihloff A.S. et al., 2010). 
 
These data were confirmed in 2013 by a systematic literature review that assessed for Europe a 
39.7% overall prevalence of HPV oropharyngeal cancer, demonstrating also a substantial 
increase over the time from 35.3% before year 2000 to 73.1% after year 2005 and a 23.7% 
overall prevalence of HPV non-oropharyngeal cancer, demonstrating also a substantial decrease 
over the time from 23.6% before year 2000 to 11.7% after year 2005 (Mehanna H. et al., 2013). 
 
 
 

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 Role of HPV in the carcinogenesis of SCCHN 
 
Tumor carcinogenesis in SCCHN involves dynamic interactions among many factors. Exposure 
of the upper aerodigestive tract to alcohol or tobacco is one of the preponderant risk factors for 
SCCHN, and exposure to both increases the risk beyond what would be expected if the agents 
simply had additive effects (Cann C.I. et al., 1985).  
Another common risk factor is alteration of the function of the p53 tumor suppressor gene, 
which may be caused by either gene mutation or infection with an oncogenic type of human 
papillomavirus (HPV) (Brachman D.G. et al., 1992), (Gillison M.L. and Shah K.V., 2001). 
In some patients, particularly those with oropharyngeal cancer not associated with p53 mutation 
or the molecular impacts of alcohol and tobacco, HPV infection can cause head and neck cancer 
even in the absence of other molecular alterations (Haddad R.I. and Shin D.M., 2008), (D'Souza 
G. et al., 2007). All of these risk factors are likely to result from and contribute to suppression 
of the patient’s immune system, as is the tumor itself (Alhamarneh O. et al., 2008). 
Studies show that an infection with high-risk HPV is an independent risk factor for the 
development of SCCHN and needs to be considered along with the traditional risk factors such 
as tobacco abuse or alcohol (D'Souza G. et al., 2007), (Gillison M.L. et al., 2000b).  
 
HPV-16 is the far most common type detected in oropharyngeal cancer accounting for 90–95% 
of the HPV positive tumors (Marur S. et al., 2010), (Kreimer A.R. et al., 2005). High-risk HPVs 
produce 2 oncoproteins, E6 and E7, which are necessary for viral replication through their 
proliferation stimulating activity and play a key role in malignant transformation. The E6 
oncoprotein binds and induces the degradation of the p53 tumor suppressor protein via an 
ubiquitin-mediated process disrupting the p53 pathway which leads to uncontrolled cell cycle 
progression (Chung C.H. and Gillison M.L., 2009), (Havre P.A. et al., 1995). The HPV E7 
protein binds and degrades the retinoblastoma protein (pRb), preventing it from inhibiting the 
transcription factor E2F resulting in loss of cell cycle control. Furthermore, the functional 
inactivation of Rb results in upregulation of the p16-protein. P16 is encoded by the CDKN2A 
tumor suppressor gene and regulates the activity of Cyclin D-CDK4/6 complexes that 
phosphorylate Rb leading to release of the transcription factor E2F which initiates cell cycle 
progression. HPV-positive tumors are characterised by high expression of high levels of p16 
(Nevins J.R., 2001). The p16 protein can be detected by immunohistochemistry, and since 
several studies have shown a very high correlation (> 90%) to HPV-positivity in oropharyngeal 
tumors, it has been suggested as a clinically useful sorrogate marker (Mellin Dahlstrand H. et 
al., 2005), (Klussmann J.P. et al., 2003) 
 
In head and neck cancer caused by the traditional risk factors, tobacco and alcohol, p53 is 
commonly mutated (Ahomadegbe J.C. et al., 1995), (Carlos de Vicente J. et al., 2004) and 
9p21-22 is lost early in carcinogenesis resulting in the loss of the tumor suppressing gene p16 
(Kim S.H. et al., 2007). In contrast, HPV-positive head and neck tumors have decreased 
expression of wild-type p53 due to the inactivation and degradation by the E6 oncoprotein. 
 
 HPV vaccine 
 
Many diverse vaccine platforms have been evaluated in clinical trials; including injection of 
peptides or proteins, injection of recombinant viruses or other recombinant micro-organisms, 
delivery of killed tumor cells, or delivery of protein or peptide-activated dendritic cells (DCs) 
to the patient. Each of them has strengths and weaknesses that can be influenced by the 
particular tumor-associated antigen that is targeted, the disease and disease stage, the clinical 

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trial endpoint, and whether the vaccine is evaluated in combination with an immune stimulant, 
an inhibitor of immune suppression, or another mode of cancer therapy (Schlom J., 2012).  
 
Two prophylactic vaccines have been developed against HPV infection in females; one is a 
quadrivalent vaccine (Gardasil) and the other is a bivalent vaccine (Cervarix). Both are 
approved for the prevention of HPV-related diseases.  
Vaccine efficacy is measured only by the prevention of virologic infection or related clinical 
events. Excellent antibody responses have been reported following immunization with both 
quadrivalent and bivalent vaccines (Villa L.L. et al., 2006), (Harper D.M. et al., 2006), 
(GlaxoSmithKline Vaccine H.P.V.S.G. et al., 2009). 
 
To date, few antitumor vaccines for SCCHN have been clinically evaluated. The emphasis is 
on dendritic cell-based vaccines, largely because of enhanced immunogenicity of epitopes 
presented by adoptively-transferred DC to responder T cells in vivo. Delivery of such antitumor 
vaccines in combination with conventional therapies and in the setting of a minimal residual 
disease to SCCHN patients takes advantage of exquisite specificity of the immune system at 
the time when tumor-induced suppression is reduced. Vaccine-driven generation, long-term 
survival and maintenance of tumor-specific immune cells are the objectives that antitumor 
vaccines have to realize to be clinically beneficial in SCCHN (Whiteside T.L., 2007). 
 
Early data suggest that targeting E6 and E7 with vaccine-based approaches is feasible and 
efﬁcacious. A phase I study attempted to combine HPV-16 derived peptides with the melanoma 
differentiation antigen MAGE-A3 into a therapeutic vaccine (Voskens C.J. et al., 2012). 
Although there were no clinical responses in this small study, immune responses directed 
against the HPV epitopes targeted by the vaccine were detected, including T-cell responses in 
4 of 5 treated patients. An additional preclinical study demonstrated the feasibility of inserting 
the E7 gene within a viral plasmid in a DNA-based HPV-targeting vaccine (Peng S. et al., 
2010).  
 
Vaccines targeting HPV are also being explored for a range of premalignant and malignant 
gynecologic diseases, and these ﬁndings could potentially be applicable to HPV-associated 
head and neck cancers (Kenter G.G. et al., 2009). Vaccination strategies are also being tested 
in HPV-negative malignancies; preliminary testing of a dendritic cell vaccine targeting p53 
epitopes was reported recently (Andrade P. et al., 2009). 
 
 PD-1 and PD-L1 pathway and immune responses 
 
PD-1 is a negative regulator of T-cell activity that limits the activity of T cells at a variety of 
stages of the immune response when it interacts with its two ligands, PD-L1 and PD-L2 (Ishida 
Y. et al., 1992), (Freeman G.J. et al., 2000), (Keir M.E. et al., 2006). When engaged by a ligand, 
through phosphatase activity, PD-1 inhibits kinase-signaling pathways that normally lead to T-
cell activation. A number of antibodies that disrupt the PD-1 axis have entered clinical 
development. PD-L1 is also believed to exert negative signals on T cells by interacting with B7 
(Butte M.J. et al., 2007), and PD-L1-blocking antibodies prevent this interaction. Immune 
checkpoint inhibitors also enhance the function of tumor-infiltrating lymphocytes (TILs), which 
augments antitumor immunity within the tumor microenvironment. The presence of TILs has 
been correlated with better prognosis in many cancer types, including bladder (Tsujihashi H. et 
al., 1988), (Lipponen P.K. et al., 1992), (Sharma P. et al., 2007), lung (Geng Y. et al., 2015), 
breast (Adams S. et al., 2014), ovarian (Zhang L. et al., 2003), renal  ((Li Y. et al., 1998), colon 

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(Maby P. et al., 2015), and esophageal (Liu J.Y. et al., 2015) carcinomas. Thus, PD-L1+ TILs 
have been shown to be indicators of response to immune checkpoint blockade, and a lack of 
TILs may be a predictive marker for lack of response to PD-1/L1 blockade (Curran M.A. et al., 
2010) (Huang R.R. et al., 2011), (Herbst R.S. et al., 2014). 
  
 
 Investigational medicinal products (IMPs) 
 
The two investigational medicinal products evaluated in the present trial are TG4001 and 
avelumab. 
 
 TG4001  
 
TG4001 is a therapeutic recombinant vaccine/immunotherapy product based on the non-
propagative highly attenuated vaccinia vector Modified Vaccinia virus Ankara (MVA) whose 
genome, a single linear double-stranded DNA molecule of approximately 178 kilobase pairs 
(Antoine G. et al., 1998) contains inserted transgenes coding for three proteins: HPV antigens 
E6 and E7 onco-proteins modified to remove their oncogenic potential and human interleukin-
2 (IL-2) as an adjuvant. 
 
The modified forms of E6 and E7 proteins each lack the region known to interact with tumor 
suppressor proteins p53 and Rb, respectively (Munger K. et al., 1989), (Crook T. et al., 1991) 
and are joined to secretory signal and membrane anchoring domains in order to direct the 
targeting of these proteins toward the cytoplasmic membrane.  
 
The mode of action is to activate the adaptive immune system towards cells expressing E6 and 
E7 and weeding out of infection through IL-2.  
 
1.2.1.1. Summary of preclinical data 
 
Preclinical studies have demonstrated that the recombinant MVA is a non-replicative virus and 
stimulates the innate immunity through IFN-gamma induction. Moreover the human cytokine 
IL2 is a growth factor for T lymphocytes and natural killer cells. The E6 and E7 HPV-16 genes 
fused to heterologous sequences encoding secretory signal and membrane-anchoring domains 
thus causing the elicitation of antigen specific Cytotoxic T lymphocytes (CTL) and enhancing 
the immunogenicity through improved antigen presentation. E6 and E7 are continuously 
expressed by HPV+ cancer cells and their expression is required for maintenance of the 
malignant phenotype. This provides higher efficacy specifically against HPV infected cells 
without any interaction with normal cells. 
 
The antitumor efficacy of TG4001 was assessed in C57Bl/6 mice engrafted with TC1 tumor 
cells, primary lung cells from C57Bl/6 mice immortalized by expression of HPV-16 E6 and E7 
(Halbert C. et al., 1991) and then transformed with the activated RAS oncogene. This 
transformation process mimics the natural sequence in the pathogenesis of cervical cancer in 
which HPV-16 plays a critical role in carcinogenesis (Halbert C. et al., 1991). 
TG4001 was demonstrated to have CD8+ T cell-dependent anti-tumor activity and to confer 
immunity against TC1 tumors expressing wild-type HPV-16 E6 and E7 genes (Pecheur C. and 
Bizouarne N., 2000). 

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Preliminary data suggested also that TG4001 does cross-react with HPV-16,31,33,35, and 52 
genotypes. 
The mechanism by which the immune system may induce regression of HPV-induced lesions 
was investigated and CD8+ T-cell response was shown to be critical for anti-tumor efficacy 
(Paul S., 2007).  
 
The effect of the route of administration as a function of the administered dose was studied in 
mice in immunotherapy experiments (Balloul J.M. and Pecheur C., 2006), (Bizouarne N., 
1998a). The most efficient route was shown to be intraperitoneal, with 100% 
immunoprophylaxis and 82% tumor rejection. However, the intraperitoneal route is not a viable 
commercial option for patient administration. Further data show that intramuscular (IM) and 
subcutaneous (SC) administration were both also effective: SC route is more efficient than the 
IM route under the conditions of the study (Bizouarne N., 1998b), (Balloul J.M. and Pecheur 
C., 2007).  
 
Excretion occurs through urine. Neither absorption/pharmacokinetic parameters or metabolism 
studies were conducted. 
 
TG4001 safety profile was investigated for its systemic toxicity and local tolerance in mice, 
rats, and rabbits. Except for slight to moderate irritant effects (erythema, and/or edema) at the 
injection site, changes included decreased reticulocytes and lymphocytes, and an increased 
spleen weight that correlated with lymphoid hyperplasia. TG4001 demonstrated an acceptable 
safety profile in doses up to 2676-fold of the maximum human dose. (Pecheur C., 1998b), 
(Pecheur C., 1998a) (Kaiser S., 2007). Focal or maculate erythema, hyperkeratosis, and 
follicular hypertrophy/hyperplasia were observed at the application site and blue skin was 
observed at application site and head. (Christ M., 2001). No concerns of effects on central 
nervous, respiratory, and cardiovascular systems. Reproductive and developmental toxicity 
standard genotoxicity studies were not conducted. No oncogenic potential of TG4001 was 
evident (Balloul J.M., 1998), (Menguy T., 2009).  
 
1.2.1.2. Summary of TG4001 efficacy data 
 
TG4001 was investigated in gynaecological conditions.  
Three Phase I multiple ascending dose studies have been conducted and were designed to 
determine the maximum tolerated dose (MTD), safety, local (dysplastic cervical tissues) and 
systemic immune responses (TG4001.01, TG4001.02, and TG4001.03) and five phase II 
studies (See Table 1-1) to determine safety and efficacy (TG4001.04, TG4001.05, TG4001.06, 
TG4001.07 and NV25025), 3 of these studies also examined immune response.  
 
The Phase I clinical studies were conducted in a total of 18 patients with either cervical disease 
including grade 3 CIN (TG4001.01) or different stages of cervical cancer (TG4001.02 and 
TG4001.03). Patients received repeated IM injections of TG4001 at one of the following dose 
levels: 5 x 105 PFU, 5 x 106 PFU, or 5 x 107 PFU. 
 
Among the 5 phase II studies, 4 were considered as not conclusive (See Table1-1) but the fifth 
Phase II (NV25025) trial in HPV-16 associated cervical intraepithelial neoplasia (CIN) grade 
2/3 demonstrated a proof of concept that TG4001 had higher activity and efficacy compared to 
placebo in terms of histologic resolution and response rates as well as viral clearance. The dose 
that was used in this phase II trial of HPV-16 associated CIN grade 2/3 patients was 5 x 107 

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PFU. Moreover, the therapeutic vaccine/immunotherapy product was demonstrated to be safe 
with no major toxicities, apart from injection site reaction (Brun J.L. et al., 2011). 
 
Among the phase II studies, TG4001.04, was the only evaluating the efficacy and safety of 
TG4001 in cervical cancer. It was a randomized, multicenter study in 30 hispanic women with 
HPV-16 positive locally advanced cervical cancer resistant to or relapsing after radiotherapy. 
Of the 16 patients included in the per protocol analysis, only two met the primary efficacy 
criteria, experiencing stable disease at Month 6.  
 
Table 1-1 : Summary of Phase II clinical trials with TG4001 
Study # 
Study design 
Selected 
population 
Schedule of 
administration, dose 
Number of 
patients 
Key results 
TG4001.04 
Open-label 
phase II  
Women with HPV-
16 positive cervical 
cancer resistant to 
or having relapsed 
after radiotherapy 
One SC injection on 
Days 1, 8, and 15 
5x105 
PFU 
(initial 
safety 
phase) 
and 
5x106 PFU (efficacy) 
N=30  
age 27-82 
yrs 
2/16 stable disease at 
6 
months 
(PP 
population) 
No clinical significant 
effect of 5x106 PFU 
TG4001.05 
Open-label 
phase II 
Women with HPV-
16 positive grade 
2/3 
Cervical 
intraepithelial 
neoplasia (CIN2/3) 
One SC injection on 
Days 1, 8, and 15  
5x105 PFU and 5x107 
PFU 
N=31 
Age 31-48 
yrs 
7/17 
early/partial 
regression of baseline 
lesions at 6 t 8 weeks 
at 5x107 PFU (dose 
effect) 
TG4001.06 
Randomized, 
open-label, 
phase II 
Women with HPV-
16 positive grade 3 
vulvar intraepithelial 
neoplasia 
(VIN) 
except 
Bowen’s 
disease 
One SC injection on 
Days 1, 8 and 15 
5x106 PFU of TG4001 
or Placebo 
N=20 
Age 27-58 
yrs 
No 
clinically 
significant effect of 
5x106 PFU 
TG4001.07 
Open–label 
phase II 
Women with HPV-
16 positive grade 
2/3 
Cervical 
intraepithelial 
neoplasia (CIN2/3) 
One SC injection on 
days 1,8, and 15 of 
TG4001 at  5x107 PFU 
N=21  
Age 25-44 
yrs 
10/21 responders at 6 
months 
NV 25025 
Randomized 
double 
blind 
placebo 
controlled 
parallel group 
multicenter 
phase II 
Women 
with 
histologically 
confirmed diagnosis 
of 
CIN2 
or 
3 
associated with a 
current 
single 
or 
multiple 
high 
risk 
HPV infection 
One SC injection on 
Days 1, 8 and 15 of 
TG4001 or placebo at 
5x107 PFU 
N= 206 
Age 18-60 
yrs 
11/55 
complete 
responders 
at 
6 
months. 
Significant 
effect 
compared to placebo 
 
1.2.1.3. Summary of TG4001 safety data 
 
The overall safety profile of TG4001 is based on data from completed studies of a total of 313 
subjects, either healthy volunteers (n=66) or patients with CIN 2/3 (n=194), cervical carcinoma 
(N=42) or VIN (N=11), treated with TG4001 in monotherapy or in combination with 
immunomodulator imiquimod.  
Among those subjects, 18 (5.8%) received injections via IM route in 3 phase I studies and 295 
(94.2%) received injections via SC route in one single-blind phase I study, in 4 open-label phase 
II studies and in one double-blind placebo-controlled phase II study. 
 
TG4001 was well tolerated up to highest dose tested of 5 x 107 PFU administered to patients 
either weekly or every 3 weeks up to 7 weeks, with a maximum of 6 injections.  
 

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The most frequently adverse drug reactions (ADRs) reported as related to TG4001 were 
common vaccine-associated reactions. The most frequent ones observed in patients receiving 
IM administrations (18 patients, incidence ≥10%) being pain at the injection site (27.8%), 
fatigue (11.1%) and feeling of body temperature change (11.1%). The most frequently observed 
ADRs in patients receiving SC administrations (295 patients, incidence ≥5%), were injection 
site reaction (ISRs) (73.9%), injection site erythema (9.5%), injection site inflammation (6.4%), 
headache (5.4%), and lymphadenopathy (5.1%). Most of these events were of mild to moderate 
intensity (grade 1 or 2). 
Most ISRs were reported as “mild” or “moderate”, all were considered probably related to study 
treatment, and all resolved without sequelae. 
 
In the indications for which TG4001 was studied, all of the serious AEs (SAEs) and deaths 
were considered unrelated to the study treatment, except of two:  
• In study NV25025 (patients with CIN 2/3) one SAE, lymphadenopathy, was assessed 
by the investigator as possibly related to TG4001. 
• In study TG4001.04 (patients with late-stage cervical cancer with resistance to or 
relapse after radiotherapy) one SAE, renal failure was assessed by the investigator as 
possibly related to TG4001. This SAE was as well assessed by the investigator as 
possibly related to the underlying disease as the patient presented at baseline cervix 
tumor with extended lymph nodes involvement and bilateral renal obstruction. The 
sponsor considered renal failure as unlikely related to TG4001 since there is a plausible 
and more likely relationship between CxCa and the patient’s evolution, based on 
baseline disease. 
The deaths that occurred were in patients with advanced cervical carcinoma or late-stage 
cervical cancer, resistant to or relapsed after radiotherapy; there were no reports of deaths in 
CIN2/3 patients treated with TG4001. 
 
Long term safety data were collected from subjects enrolled from both studies NP21903 (phase 
I in healthy volunteers) and NV25025 (phase II in CIN 2/3 patients). Overall duration of safety 
follow-up extended to a maximum of 946 days and no safety concern was raised over this 
period. 
 
For more details and updated information refer to TG4001 Investigator’s Brochure.  
 
 Avelumab  
 
Avelumab (also known as MSB0010718C) is an investigational fully human anti-PD-L1 IgG1 
monoclonal antibody (MoAb).  
Avelumab is currently in clinical investigation.   
 
Avelumab has 2 main mechanisms of action for exerting its anti-tumor effects:  
- 
PD-L1 on tumor cells can interact with PD-1 or B7-1 on activated T cells. These 
interactions have been shown to significantly inhibit T cell activities. Therefore, 
blocking PD-L1 interaction with PD-1 or B7-1 by anti-PD-L1 can release T cells from 
immunosuppression, and lead to elimination of tumor cells by T cells.  
- 
Tumor cells may express high levels of PD-L1 on their surface compared with normal 
tissues. As a fully human IgG1 MoAb, avelumab has antibody-dependent cell-mediated 
cytotoxicity (ADCC) potential. Upon binding to PD-L1 on tumor cells and binding with 

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their Fc part to Fc-gamma receptors on leukocytes, avelumab can trigger tumor-directed 
ADCC.  
Therefore, blocking PD-L1 inhibitory mechanisms by interactions with not only PD-1 but also 
the other ligand, B7-1, avelumab may offer unique therapeutic potential compared with MoAbs 
targeting PD-1. 
 
1.2.2.1. Summary of preclinical data 
 
The nonclinical pharmacology studies have shown that avelumab functionally enhances T cell 
activation in vitro and significantly inhibits the growth of PD-L1 expressing tumors in vivo. 
Avelumab binds to human PD-L1 with a high affinity of 0.7 nM and not to any other B7 family 
proteins, and competitively blocks the interaction of PD-L1 with PD-1. The in vitro study 
results have shown that by binding to PD-L1, avelumab effectively enhances T cell activation 
as measured by interleukin (IL)-2 or interferon-gamma (IFN-gamma production). In addition, 
as a fully human IgG1 antibody, avelumab has the potential to trigger the ADCC against target 
cells expressing PD-L1.  
 
As a monotherapy, avelumab has demonstrated anti-tumor activity against murine MC38 colon 
carcinoma tumors that are characterized by a high level of PD-L1 expression. A dose-dependent 
trend was observed, and 400 µg per dose (20 mg/kg, approximately) was identified as the 
optimally effective dose when given every third day for 3 total doses. 
 
The in vivo anti-tumor effects were found to be primarily mediated by CD8+ T cells as 
evidenced by the observation that in vivo depletion of this cell type completely abrogated the 
anti-tumor efficacy of avelumab. The contribution of ADCC as a potential mechanism of anti-
tumor activity was further demonstrated in vivo using a deglycosylated version of avelumab to 
abrogate fragment crystalline (Fc) receptor binding or via the systemic depletion of natural 
killer (NK) cells. In both settings, loss of in vivo ADCC potential significantly reduced the anti-
tumor activity. 
 
Various immunomonitoring assays were incorporated into the in vivo studies. Treatment with 
avelumab resulted in a consistent increase in the percentage of CD8+PD-1+ T cells and an 
increased frequency of CD8+ T cells with an effector memory (TEM) phenotype as determined 
by flow cytometry. Furthermore, these changes correlated with the anti-tumor effect. Increases 
in tumor antigen-specific T cell responses, as measured by enzyme-linked immunosorbent spot 
and pentamer immunoassays, were evident following treatment with avelumab. Hence, 
increases in CD8+PD-1+ T cells, CD8+ TEM cells, and antigen-specific T cell responses, may be 
leveraged as pharmacodynamics (PD) biomarkers with translational relevance to the clinical 
setting. 
 
As expected for a MoAb binding to a cellular target, avelumab demonstrated pronounced non-
linear pharmacokinetic (PK) characteristics in mice and monkeys in single dose studies at doses 
below 20 mg/kg, suggesting a combination of first order catabolic clearance and saturable 
target-mediated clearance. Toxicokinetic data from repeated dose toxicity studies in mice, rats, 
and monkeys indicated that the PK of avelumab was linear within the dose range of 20 to 140 
mg/kg, suggesting that the target mediated clearance could be saturated when higher doses than 
20 mg/kg are administered. Similar terminal half-lives (t1/2) of approximately 60 to 70 hours 
were observed in toxicity studies in mice and monkeys. 

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The toxicological profile of avelumab was evaluated in repeat-dose toxicity studies of 4-week 
duration with once weekly IV bolus injection/infusion of avelumab in mice, rats, and 
cynomolgus monkeys. A repeat-dose toxicity study with intermittent once weekly IV infusion 
of avelumab over 13 weeks followed by an 8-week recovery period in cynomolgus monkeys 
was also conducted. In addition, in vitro cytokine release assays (CRA) in human and 
cynomolgus monkey whole blood and peripheral blood mononuclear cells (PBMCs) followed 
by an optimized CRA in phytohemagglutinin (PHA) pre-stimulated PBMCs from 16 human 
volunteers was completed. Tissue cross reactivity (TCR) studies in normal human and 
cynomolgus monkey tissues have also been performed. 
In cynomolgus monkeys neither in the pilot 4-week IV repeat-dose toxicity study nor in the 
pivotal 13-week study, clinical signs of hypersensitivity have been seen after repeated treatment 
with avelumab at dose levels of 20, 60, and 140 mg/kg, respectively. For the pilot 4-week study 
as well as for the pivotal 13-week IV repeat-dose toxicity study, a no observed adverse effect 
level (NOAEL) of 140 mg/kg for systemic toxicity was established. 
 
Initial CRA in human and cynomolgus monkey whole blood and PBMCs revealed no clear-cut 
evidence for release of pro-inflammatory cytokines. However, a subsequent, optimized CRA 
demonstrated evidence of potential cytokine release in PHA pre-stimulated PBMCs. 
1.2.2.2. Pharmacokinetics and metabolism 
 
Pharmacokinetics following the first 1-hour infusion and dose proportionality of avelumab 
have been characterized in 57 Caucasian patients treated in the dose escalation and expansion 
cohort of the Phase I Trial EMR100070-001 by standard non-compartmental analysis based 
on rich serum concentration-time data obtained over a complete dosing interval of 2 weeks (= 
tau). The analysis of these data revealed that the exposure parameters maximum concentration 
observed post-dose (Cmax) and area under the concentration-time curve (AUCtau) increased 
with the doses in a linear fashion. 
The apparent terminal half-life (t1/2) was 69 hours (mean) ± 21 hours (standard deviation) for 
1 mg/kg, 84 ± 22 hours for the 3 mg/kg, 106 ± 29 hours for 10 mg/kg, and 134 ± 74 hours for 
the 20 mg/kg dose. Taking into account the variability, the t1/2 of the 10 and 20 mg/kg doses 
can be regarded as similar, indicating that target mediated elimination does not increase at 
these doses. This implies that target occupancy is likely to be high at these 2 doses throughout 
the dosing interval.  
Trough concentrations (Cmin) were obtained for the majority of patients enrolled in the trial. 
The median Cmin at the end of the first cycle after administration of the 10 mg/kg dose was 20 
µg/mL (n=256). This median Cmin increased during the subsequent cycles to 24 µg/mL (second 
cycle; n=233), 26 µg/mL (third cycle; n=167), and remained between 24 and 37 µg/mL during 
the subsequent cycles (n=22 to 114) indicative for no significant accumulation with the 
biweekly dosing scheme. Median Cmin after the 3 mg/kg dose were 3.7µg/mL after the first 
dose, 3.9 µg/mL after the second dose and 8.3 µg/mL after the third dose (n=7 to 12), though 
some trough values below 1 µg/mL were observed, as well as antidrug antibodies in at least 1 
patient in this dose group on day 85 of the treatment period, accompanied by loss of 
quantifiable exposure. Median trough concentrations after the 20 mg/kg dose were 44, 70, and 
77 µg/mL after the first, second, and third dose, respectively (n=14 to 19). 
 
For the 10 mg/kg dose, the volume of distribution was 55 mL/kg (mean) ± 12 mL/kg (standard 
deviation) and total systemic clearance was low (0.38 mL/h/kg ± 0.11 mL/h/kg). 

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Avelumab, as a MoAb, is not expected to have a direct drug-drug interaction (DDI) effect on 
other small molecule drugs. In addition, like other checkpoint inhibitors in the class, avelumab 
is not considered to be a cytokine modulator, which was confirmed by cytokine data collected 
from EMR 1000700-001.  
Based on the acquired information, avelumab is unlikely to have an effect on drug metabolizing 
enzymes or transporters in terms of inhibition or induction. It is also not expected to have DDI 
with other drugs because it is primarily metabolized through catabolic pathways and is not 
expected to affect the expression of CYP450 enzymes. 
 
For more details and updated information refer to the Investigator’s Brochure. 
 
1.2.2.3. Summary of safety data  
 
The safety of avelumab was investigated in 4 currently ongoing clinical trials in more than 1400 
patients with solid tumors: 
• EMR 100070-001: A Phase I, open-label, multiple ascending dose trial to investigate the 
safety, tolerability, pharmacokinetics, biological and clinical activity of avelumab in patients 
with metastatic or locally advanced solid tumors and expansion to selected indications (1353 
patients treated with avelumab, who received at least 1 dose and were followed up for at 
least 4 weeks from the first dose at the cutoff date of 05 November 2015) 
• EMR 100070-002: A Phase I trial to investigate the tolerability, safety, pharmacokinetics, 
biological and clinical activity of avelumab in Japanese patients with metastatic or locally 
advanced solid tumors, with expansion part in Asian patients with gastric cancer (52 patients 
have been treated with avelumab at the cutoff date of 17 December 2015). 
• EMR 100070-003: A Phase II, single arm, open-label, multicenter trial to investigate the 
clinical activity and safety of avelumab in patients with Merkel cell carcinoma (MCC) (88 
patients have been treated with avelumab at the cutoff date of 17 December 2015) 
• EMR 100070-004: A Phase III open-label, multicenter trial of avelumab versus docetaxel in 
patients with non-small cell lung cancer who progressed after a platinum-containing doublet 
(75 patients treated with avelumab or docetaxel at the cutoff date of 17 December 2015). 
 
For the sake of the proposed trial, safety data of the large EMR 100070-001 phase I study in 
solid tumors are presented in the section below.  
 
For more details and updated information on full safety data, please refer to the latest 
available version of the avelumab Investigator’s Brochure and APPENDIX V Avelumab 
Summary of Safety Profile). 
 
As of the safety cutoff date of 05 November 2015, 1353 patients have received at least 1 dose 
of avelumab at doses ranging from 1.0 to 20 mg/kg in the Phase I Trial EMR 100070-001, of 
which 1315 have received the proposed dose of 10 mg/kg (15 in the dose escalation part of the 
study and 1300 patients in the pooled expansion cohort). 
 
- 
In the dose escalation phase of the trial: 
 
The median avelumab treatment duration was 12.0 weeks, and the median number of avelumab 
infusions received was 6.0. As of 05 November 2015, all 53 patients (100%) discontinued trial 
treatment. The primary reason for treatment discontinuation was disease progression (38 

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patients; 71.7%), followed by treatement emergent adverse event (TEAE) (10 patients; 18.9%), 
withdrawal of consent and deaths (2 patients each; 3.8%). 
There was no evidence of differences in the safety profile across all administered dose levels 
from 1 mg/kg to 20 mg/kg. The MTD was not reached.  
 
The most frequently observed treatment related TEAE was fatigue reported in 21 patients 
(39.6%), followed by influenza-like illness in 11 patients (20.8%), and pyrexia in 8 patients 
(15.1%). Nine of the 53 patients (17.0%) experienced at least 1 Grade ≥ 3 treatment-related 
TEAE. These included event terms of autoimmune disorders (3 patients; 5.7%), aspartate 
aminotransferase (AST) increased and blood creatine phosphokinase (CPK) increased (each in 
2 patients; 3.8%), and fatigue, abdominal pain lower, lipase increased, amylase increased, 
alanine aminotransferase (ALT) increased, blood alkaline phosphatase increased, and 
lymphocyte count decreased (each in 1 patient 1.9%). Of the 9 patients (17.0%) who had Grade 
≥ 3 treatment-related TEAEs, 7 (13.2%) had Grade 3 events, 2 (3.8%) had Grade 4 events 
(blood CPK increased and autoimmune disorder), and no Grade 5 treatment-related TEAEs 
were observed. 
Thirty-one patients (58.5%) died as of the data cutoff date (05 November 2015). No deaths were 
due to treatment-related TEAEs. 
- 
In the pooled expansion cohort: 
 
The 1300 patients comprising the pooled expansion cohort includes patients from 16 tumor 
expansion cohorts. 
 
Treatment exposure: 
As of 05 November 2015, the median avelumab treatment duration was 11.5 weeks and the 
median number of avelumab infusions was 5.0; 425 of the 1300 patients (32.7%) remained on 
trial treatment. The primary reason for treatment discontinuation was disease progression (608 
patients; 46.8%), followed by TEAEs (122 patients; 9.4%). Other reasons for treatment 
discontinuation included deaths (58 patients; 4.5%), withdrawal of consent (40 patients; 3.1%), 
protocol non-compliance (7 patients; 0.5%), and lost to follow-up (3 patients; 0.2%). For 37 
patients (2.8%), the reason for treatment discontinuation was labelled as “other” in the database 
at the time of the data cutoff.  
 
Treatment-emergent adverse events (TEAEs): 
Of the 1300 patients treated in the pooled expansion cohort, 1200 (92.3% experienced at least 
one TEAE. The most frequently reported TEAEs (incidence ≥ 10%) were fatigue (27.4%), 
followed by nausea (21.2%), infusion-related reaction (16.2%), diarrhea (15.8%), and 
constipation (15.7%). 
 
Treatment-related TEAEs were observed in 813 (62.5%) patients, the most commonly observed 
(incidence > 2%) being fatigue (212 patients, 16.3%), infusion-related reaction (209 patients, 
16.1%), nausea (108 patients, 8.3%), chills (102 patients, 7.8%), diarrhea (79 patients, 6.1%), 
and pyrexia (72 patients, 5.5%). Grade ≥ 3 treatment-related TEAEs were observed in 124 
patients (9.5%) (See Table 1-2). 
 
The most frequently reported Grade ≥ 3 treatment related TEAEs were gamma-glutamyl 
transferase increased (GGT) and infusion-related reaction (each occurred in 9 patients; 0.7%). 
 

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Infusion-related reactions including drug hypersensitivity reactions and immune-mediated 
adverse reactions have been identified as expected adverse drug reactions of avelumab. The 
safety profile of avelumab is consistent with findings reported for other anti-PD-1 or anti-PD-
L1 antibodies. 
 
Table 1-2 : Most Frequently Reported (Incidence ≥ 2% in the Pooled Expansion Cohort) 
Treatment-Related TEAEs in the Pooled Expansion Cohort  
MedDRA PT 
Pooled Expansion Cohort 
(n=1300) 
n (%) 
Patients with at least 1 AE 
813 (62.5) 
Fatigue 
212 (16.3) 
Infusion-related reaction 
209 (16.1) 
Nausea 
108 (8.3) 
Chills 
102 (7.8) 
Diarrhoea 
79 (6.1) 
Pyrexia 
72 (5.5) 
Decreased appetite 
60 (4.6) 
Arthralgia 
53 (4.1) 
Vomiting 
46 (3.5) 
Hypothyroidism 
45 (3.5) 
Influenza like illness 
42 (3.2) 
Pruritus 
40 (3.1) 
Myalgia 
37 (2.8) 
Rash 
36 (2.8) 
Headache 
34 (2.6) 
Anaemia 
30 (2.3) 
Asthenia 
29 (2.2) 
Aspartate aminotransferase increased 
26 (2.0) 
Constipation 
26 (2.0) 
MedDRA: Medical Dictionary for Regulatory Activities; PT: preferred term; TEAE: treatment-emergent adverse 
event. Safety Population.  
 
 
Serious adverse events: 
As of 05 November 2015, 509 of 1300 patients (39.2%) in the pooled expansion cohort had at 
least 1 serious TEAE and 71 (5.5%) experienced at least one treatment-related serious TEAEs. 
These included infusion-related reaction (11 patients; 0.8%), pneumonitis (8 patients; 0.6%), 
pyrexia and dyspnea (each in 5 patients; 0.4%), autoimmune hepatitis (3 patients; 0.2%), and 
asthenia, blood creatine phosphokinase increased, abdominal pain, colitis, diarrhea, vomiting, 

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hyponatremia, adrenal insufficiency, and non-cardiac chest pain (each in 2 patients; 0.2%). All 
other treatment-related serious TEAEs were reported in a single patient (0.1%) only. 
 
Deaths: 
As of 05 November 2015, 466 deaths (35.8%) occurred in the pooled expansion cohort. The 
majority of deaths were due to progressive disease (360 patients; 27.7%). A total of 5 deaths 
(0.4%) due to TEAEs related to trial treatment were considered as primary reason of the death 
by the investigator. Two additional cases of death were reported and assessed as treatment-
related, but the treatment related TEAEs were not considered as the primary reason of the death. 
 
Potential immune related AEs (irAEs): 
Table 1-3 shows incidences of the treatment-related TEAEs, considered and described as 
immune-mediated adverse reactions observed in the pooled expansion cohort in the ongoing 
trial EMR 100070-001 after 1300 subjects were treated with 10 mg/kg of avelumab once every 
2 weeks (cut-off date 05 Nov 2015).  Hypothyroidism was the most frequent treatment-related 
potential immune-mediated AE, which occurred in 45 patients (3.5%) in the pooled expansion 
cohort (See Table 1-3).  The majority of potential immune-mediated AEs were Grade 1 or Grade 
2 events. 
 
Risk mitigation measures have been implemented and guidelines for management of irAEs are 
provided in the trial protocol (see Section 6.5.2.6). Of note, irAEs are considered an identified 
risk of avelumab. 
 
Table 1-3 : Incidence of Treatment-Related TEAEs of Immune-Mediated Adverse  
Reactions in Trial EMR 100070-001 
 
Category 
MedDRA PT(s) 
AE of Any  
Grade 
(n=1300) 
n (%)b 
AE Grade ≥  
3 
(n=1300) 
n (%) 
Serious AE  
(n=1300) 
n (%) 
Immune-mediated 
pneumonitis 
Pneumonitis 
13 (1.0) 
4 (0.3) 
8 (0.6) 
Immune-mediated colitis 
Colitis 
4 (0.3) 
3 (0.2) 
2 (0.2) 
Immune-mediated hepatitis 
Autoimmune hepatitis 
4 (0.3) 
0 
3 (0.3) 
Immune-mediated thyroid 
disorders 
Hyperthyroidism 
7 (0.5) 
0 
1 (0.1) 
Hypothyroidism 
45 (3.5) 
0 
1 (0.1) 
Thyroiditis 
2 (0.2) 
0 
0 
Autoimmune 
thyroiditis 
2 (0.2) 
0 
0 

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Category 
MedDRA PT(s) 
AE of Any  
Grade 
(n=1300) 
n (%)b 
AE Grade ≥  
3 
(n=1300) 
n (%) 
Serious AE  
(n=1300) 
n (%) 
 
Immune-mediated skin 
reactions 
 
Rash 
36 (2.8) 
2 (0.2) 
0 
Pruritus 
40 (3.1) 
0 
0 
Rash pruritic 
8 (0.6) 
1 (0.1) 
0 
Rash generalized 
3 (0.2) 
0 
1 (0.1) 
Rash maculo-papular 
22 (1.7) 
0 
0 
Erythema 
6 (0.5) 
0 
0 
Pemphigoid 
1 (0.1) 
0 
0 
Other immune-mediated 
reactions 
Adrenal insufficiency 
5 (0.4) 
1 (0.1) 
2 (0.2) 
Myositis 
3 (0.2) 
3 (0.2) 
1 (0.1) 
Myocarditisa 
1 (0.1) 
0 
0 
MedDRA: Medical Dictionary for Regulatory Activities; PT: preferred term. 
a 
The data are from the pooled expansion cohort of the ongoing, uncontrolled Trial EMR 100070-001 (cut-off date 
05 Nov 2015). There was no event reported as myocarditis, but 1 event of autoimmune disorder including myositis and 
myocarditis. In addition, 2 cases of fatal myocarditis have been reported from trials B9991002 and EMR 100070-004 
recently.  Narratives for these cases are provided in the avelumab Investigator’s Brochure. 
  
Infusion related reaction: (See Table 1-4) 
Four patients (7.5%) in the dose escalation cohort reported an infusion-related reaction (all 
Grade 2) with an onset after the first (1 patient, 1.9%) or second (3 patients, 5.7%) infusion. 
A total of 215 out of the 1300 patients (16.5%) in the pooled expansion cohort experienced at 
least 1 episode of infusion-related reaction. Most of the events were Grade 1 (53 patients, 4.1%) 
or Grade 2 (153 patients, 11.8%) in intensity, and Grade 3 (6 patients, 0.5%) or Grade 4 events 
(3 patients, 0.2%) were less frequent. No Grade 5 events were reported.  
 
Most of the infusion-related reactions had an onset after the first (149 patients, 11.5%) or second 
(48 patients, 3.7%) avelumab infusion, and those with an onset after the third (12 patients, 0.9%) 
or fourth or later avelumab infusion (6 patients, 0.5%) were less frequent. In 23 patients (1.8%), 
avelumab treatment was discontinued because of infusion-related reaction. 
 
One hundred and ninety-four of 1259 patients (15.4%) in the pooled expansion cohort 
experienced infusion-related reaction in the presence of premedication with 50 patients (4.0%) 

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having Grade 1, 138 patients (11.0%) having Grade 2, 4 patients (0.3%) having Grade 3, and 2 
patients (0.2%) having Grade 4 events. 
 
Table 1-4 : Summary of infusion related reaction events for Trial EMR 100070-001 
 
Dose Escalation Patients  
(n=53) 
n (%) 
Pooled Expansion Patients  
(n=1300) 
n (%) 
Number of patients with at least 1 event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
4 (7.5) 
0 
4 (7.5) 
0 
0 
0 
215 (16.5) 
53 (4.1) 
153 (11.8) 
6 (0.5) 
3 (0.2) 
0 
Number of patients with the event leading to 
permanent treatment discontinuation 
0 
23 (1.8) 
Time related to the first onset of the event 
Infusion 1 
Infusion 2 
Infusion 3 
Infusion 4 or later 
1 (1.9) 
3 (5.7) 
0 
0 
149 (11.5) 
48 (3.7) 
12 (0.9) 
6 (0.5) 
Preferred terms of ʽInfusion-related reaction’, ʽDrug hypersensitivity’, or ʽAnaphylactic reaction’ are summarized in this 
table. A patient may have more than 1 event, but the patient is counted only once by the worst grade. 
An infusion-related reaction is assigned to a drug infusion if its onset is at the same date (but not before dosing) or the 
following day of drug infusion. 
Antidrug antibody (ADA) response  
Post-treatment samples for evaluation of ADA response were available for 39 patients from the 
dose escalation cohort and 338 patients in the pooled expansion cohort.  
Anti-drug antibody (ADA) was tested positive in 1 of 39 patients in the dose escalation cohorts 
and in 10 of 338 patients in the pooled expansion cohort. Of the 11 ADA-positive patients, 2 
patients had symptoms on the day of the infusion consistent with a possible hypersensitivity 
reaction (chills, fever, nausea, and vomiting) and may be ADA related. However, in the other 
9 ADA-positive patients, no hypersensitivity reactions were observed. 
 
Laboratory abnormalities: 
Post-baseline laboratory data abnormalities in Trial EMR 100070-001 during the treatment 
expansion phase were assessed by NCI-CTCAE grade. It should be noted that interpretation of 
the laboratory data is limited at this point in time due to various missing laboratory assessment 
data as of the safety data cutoff (05 November 2015). 
- 
Hematology 
Some hematology abnormalities of any grade were reported in the pooled expansion cohort 
with the most frequent abnormalities of anemia (74.9%) and lymphocyte count decreased 
(52.3%), followed by white blood cell (WBC) count decreased (17.2%) and platelet count 
decreased (17.0%).  
Most hematology abnormalities were mild or moderate (Grade 1 or 2). The most frequent Grade 
3 or Grade 4 abnormalities were lymphocyte count decreased in 11.4% of patients, of which 
0.5% had Grade 4 events; anemia in 4.5% of patients, all being Grade 3 events; and platelet 
count decreased in 1.1% of patients, of which 0.8% experienced a Grade 4 abnormality. 

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- 
Blood chemistry 
In the pooled expansion cohort, the most frequent blood chemistry abnormalities of any grade 
included creatinine increased (75.5%) followed by hyponatremia (41.3%), alkaline phosphatase 
increased (37.8%), hypoalbuminemia (34.0%), GGT increased (32.2%), hypertriglyceridemia 
(32.3%), AST increased (30.4%), and cholesterol high (26.8%).  
Most of the blood chemistry abnormalities were Grade 1 or Grade 2, and Grade 3 or 4 blood 
chemistry abnormalities occurred less frequently (usually with a single digit incidence or even 
lower incidence for any measurement). 
 
In conclusion, preliminary data from EMR 100070-001 comprising the pooled expansion 
cohort including patients from 16 tumor expansion cohorts showed that avelumab at doses up 
to 20 mg/kg IV every 2 weeks was well tolerated, and the dose of 10 mg/kg IV every 2 weeks 
was considered to have an acceptable safety profile for further investigation in clinical studies. 
 
Safety data obtained in the ongoing SCCHN expansion cohort including 153 patients reveals 
consistency in the overall safety profile (unpublished data, internal communication by Merck 
KGaA / EMD Serono). 
Of the 153 patients treated, 143 (93.5%) experienced at least one TEAE.  
Treatment-related TEAEs were observed in 79 (51.6%) patients, the most commonly observed 
(incidence > 5%) being fatigue (15 patients, 9.8%), pyrexia (14 patients, 9.2%), infusion-related 
reaction (13 patients, 8.5%), chills (9 patients, 5.9%), and diarrhoea (8 patients, 5.2%). Grade 
≥ 3 treatment-related TEAEs were observed in 8 patients (5.2%).  
Immune-related AEs occurred in 14 patients (9.2%), hypothyroidism (7 patients, 4.6%) and 
pneumonitis (2 patients, 1.3%) being the most frequent. 
 
1.2.2.4. Summary of clinical efficacy 
  
Currently, more than 1400 cancer patients have been treated with avelumab in the Phase Ib/II 
clinical program (Solid Tumors).  
Single agent avelumab given at 10 mg/kg Q2W has showed an acceptable safety profile and 
promising clinical activity for patients with lung, breast (Dirix L.Y. et al., 2015), ovarian, and 
gastric cancers (Chung H.C. et al., 2016), (Nashina T et al., 2016 ). 
Based on findings from the phase II JAVELIN Merkel 200 submission for marketing 
applications are planned avelumab in metastatic Merkel Cell Carcinoma. The study was 
conducted in 88 patients with chemotherapy-refractory metastatic Merkel cell carcinoma 
showing objective response rate with avelumab of 31.8%, including a 9.1% complete response 
rate. After a median follow-up of 10.4 months, 82% of patients continued to respond to therapy 
(Kaufman H.L. et al., 2016). 
 
Preliminary results from the ongoing expansion cohort in SCCHN reveal a clinical benefit in 
this heavily pre-treated patient population. 
 
For more details, please refer to the avelumab Investigator’s Brochure. 
 
 
 

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 Rationale for conducting the trial 
 
 Rationale for selecting SCCHN in the phase II of the study 
 
Head and neck cancer (HNC) is the sixth most common cancer worldwide and is ranked as the 
eighth leading cause of cancer death (Siegel R. et al., 2012). In Europe, it is estimated that there 
are approximately 143 000 new cases and > 68 000 deaths due to the disease each year 
(Globocan, 2012).  
 
Head and neck cancer is comprised of a heterogeneous group of cancers with different anatomic 
locations with squamous histology representing 95% of the cases. These tumors can be found 
in the oral cavity, the larger pharyngeal area (including the nasopharynx, oropharynx, and 
hypopharynx), and the larynx. Occasionally, other anatomic sites are involved, such as the 
paranasal sinuses, lips, salivary glands, and other areas of the head and neck and upper 
aerodigestive tract. 
 
The incidence of head and neck cancers varies widely around the world and even within 
populations. Oral and oropharyngeal cancer constitutes 3-5% of the malignancies in Europe, 
while this ﬁgure in parts of Southeast Asia and India reaches up to 40–50% (Bray F. et al., 
2002). In certain parts of Asia, such as India, HNC is the most common cancer type, even more 
common than lung cancer.  
 
Tobacco and alcohol use are the predominant risk factors for the development of carcinomas 
across all subsites of the head and neck tumors. Oncogenic viruses also play a large and 
important role in the carcinogenesis of HNC. In the last few years, there has been a rapid rise 
in the incidence of human papilloma virus (HPV) positive HNC in the Western world (Shiboski 
C.H. et al., 2005), (Marur S. et al., 2010; Nasman A. et al., 2009),(Chaturvedi A.K., 2012). 
Most of these tumors occur in the subsites of the oropharynx, including the tonsil, base of 
tongue, and soft palate by contrast, to HPV-negative tumors occuring throughout the entire 
upper aerodigestive tract.  
 
HPV-positive oropharyngeal squamous cell carcinomas of head and neck (SCCHN) represent 
a growing entity in the head and neck with distinct carcinogenesis, clinico-pathological 
presentation and survival profile. HPV-positive tumors are usually poorly differentiated and 
nonkeratinizing and have a basaloid appearance in contrast to the HPV-negative that is more 
moderately differentiated and keratinizing (Wilczynski S.P. et al., 1998),(Gillison M.L. et al., 
2000a). HPV-positive tumors also display signiﬁcantly lower levels of chromosomal mutations 
than the HPV-negative tumors (Braakhuis B.J. et al., 2004), (Smeets S.J. et al., 2006). 
Furthermore, patients with HPV-positive oropharyngeal cancers in general, especially tonsillar 
cancers, tend to be younger at time of diagnosis (Hammarstedt L. et al., 2006), (Smith E.M. et 
al., 2004), possibly with the exception of base of tongue cancers where no age difference could 
be found between the HPV-positive and HPV-negative cancer patients (Attner P. et al., 2010). 
The majority of the patients have no prior history of tobacco and/or high alcohol consumption 
and have generally a better performance status compared to the HPV-negative patients (Gillison 
M.L. et al., 2008), (Lassen P. et al., 2009). Moreover, HPV-positive tumors often present at a 
higher stage with a small T-size (T1-T2) (Lassen P. et al., 2009) but frequently there is a large, 
often cystic, nodal involvement (N+) (Goldenberg D. et al., 2008), (Lassen P., 2010) , thus, 
HPV-positive tumors are often diagnosed in clinical advanced stages (i.e., Stages III-IV) 
(Lindquist D. et al., 2007). 

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HPV-positive patients are known to have a better prognosis than HPV-negative ones. Several 
studies have also shown that HPV-positive patients are more responsive to treatment and have 
better rates of disease-speciﬁc survival than patients with traditional risk factors such as tobacco 
and alcohol (Kumar B. et al., 2007), (Weinberger P.M. et al., 2006). The reason for the better 
response to oncological treatment for patients with HPV-positive tumors may be explained by 
the presence of an intact p53-mediated apoptotic response. Another explanation is the presence 
of immunological factors related to HPV infection (Spanos W.C. et al., 2009). Nevertheless, 
there is a subgroup of the HPV-positive oropharyngeal cancers that have worse clinical 
outcome, that do not respond as well to given treatment, and have a higher rate of relapses and 
worse survival than the majority of the tumors in this group.  
 
Despite the knowledge of the heterogeneity regarding tumor aggressiveness and response to 
treatment of SCCHN, the management of patients with HPV-positive and HPV-negative 
SCCHN is today similar. The treatment depends on primary tumor location and extension and 
requires generally a multidisciplinary approach. Approximately 40% of patients with SCCHN 
present with early-stage disease. For these patients, single-modality treatment with surgery or 
radiotherapy is generally recommended (Gregoire V. et al., 2010).  
 
Most patients (60%) present with locally advanced disease at diagnosis and require a 
multidisciplinary approach using some combination of surgery, radiotherapy, and 
chemotherapy (Gregoire V. et al., 2010), but will eventually relapse, either locoregionally only, 
at distant sites only or both. A few patients with a locoregional recurrence can be salvaged by 
surgery or reirradiation. However, most patients with recurrent or metastatic (R/M) disease only 
qualify for palliative treatment. Treatment options in these patients include supportive care 
only, or in addition single agent chemotherapy, combination chemotherapy or targeted therapies 
either alone or in combination with cytotoxic agents.  
 
The prognosis for SCCHN is generally poor in the advanced stages and there has been only a 
modest improvement in recent years in the treatment. Standard treatment with radiation and/or 
chemotherapy frequently sentences the patient to life-long sequelaes such as difficulties with 
swallowing, dryness of the mouth, esophageal strictures, and osteoradionecrosis. 
 
 Rationale for the use of checkpoint inhibitors in HPV-positive SCCHN 
 
Because HPV-positive tumors are induced by a viral infection of HPV, these tumors have a 
different pathological background compared to cancer induced by traditional risk factors such 
as tobacco and alcohol. The viral infection can serve as a foreign antigen that might enhance 
the immune system’s response to the tumor. Humoral immune responses against the viral 
antigens E6 and E7 have been found frequently in HPV-positive cancer patients and can be 
correlated with increased survival, implying an important role in the immunological recognition 
of HPV (Rotnaglova E. et al., 2011). That is why HPV-associated SCCHN is considered an 
optimal entity for immunotherapy. 
 
Recently, the group of Heusinkveld et al. (Heusinkveld M. et al., 2012) discussed the important 
immunological role of HPV-16-speciﬁc systemic and local T cells. HPV-SCCHN expresses the 
two viral oncoproteins E6 and E7. These two oncoproteins are foreign to the body, so they are 
thought to have an immunogenic potential. Heusinkveld et al. evaluated the presence of 
systemic and local T cells reactive against these oncoproteins. The study included 50 patients 

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with SCCHN, 12 of which were positive for DNA of HPV-16. Almost all HPV-positive tumors 
were oropharyngeal cancers. The authors found circulating HPV-16- and p53-speciﬁc T cells 
in 17/47 and 7/45 tested patients. In 20 of these patients, T cells were isolated from tumor 
cultures and/or lymph nodes. Tumor-inﬁltrating HPV-16-speciﬁc T cells were found in six of 
eight HPV-positive tumors. In the 12 HPV-negative tumors, no HPV-16-speciﬁc T cells were 
found. In-depth analysis of the HPV16-speciﬁc T cell response revealed that this response 
comprised a broad repertoire of CD4 + T- helper type 1 and 2 cells, CD4+ regulatory T cells 
and CD8+ T cells reactive to HPV-16. The local presence of HPV-16-speciﬁc T cell immunity 
in HPV-16-induced SCCHN implicates a role in the antitumor response and supports the 
approaches for immunotherapy of HPV-positive SCCHN (Heusinkveld M. et al., 2012). 
 
A possible mechanism for tumor immune escape in HPV-positive SCCHN has been examined 
by Lyford-Pike et al (Lyford-Pike S. and . e.a., 2012). The authors provided evidence for an 
adaptive immune resistance mechanism, which is mediated trough the PD-1/PD-L1 pathway. 
In vitro studies showed that blockage of the interaction between PD-1 and PD-L1 potentiates 
the immune response and mediates preclinical antitumor activity (Fife B.T. et al., 2009), (Iwai 
Y. et al., 2002), (Lyford-Pike S. and . e.a., 2012) analyzed tumor inﬁltrating lymphocytes (TILs) 
for PD-1 expression and the PD-L1 expression in HPV-positive SCCHN. The authors showed 
that the majority of CD8+ TILs in HPV-positive SCCHN express the PD-1 co-inhibitory 
receptor and there was a higher PD-1 expression by CD4+ and CD8+ T cells in tonsil tissue as 
compared to the peripheral blood. In 20 patients with HPV-positive SCCHN, 14 (70 %) 
expressed PD-L1. A very interesting point is that the ligands PD-L1 on the tumor cells were 
predominantly located at the periphery of tumor nests, whereas only 1 of the 14 patients 
demonstrated diffuse PD-L1 expression. Furthermore the authors found an association between 
expression of ligand PD-L1 on tumor cells and tumor-associated macrophages and the presence 
of TILs. In the microenvironment of HPV SCCHN, a signiﬁcant increase of CD8-positive TILs 
and interferon-c (IFN-c) mRNA in PD-L1+ compared to PD-L1- cancers was seen. This study 
showed that the PD-1/PD-L1 interaction creates an immune-privileged site for initial virus 
infection, leading to adaptive immune resistance once tumors are established. These ﬁndings 
suggest that the blockade of this pathway could be a new approach to treat HPV-positive tumors 
(Lyford-Pike S. and . e.a., 2012). These new ﬁndings are of special signiﬁcance since the 
activity of a PD-L1 and a PD-1 antibody has been recently demontrated in two phase I trials in 
patients with advanced cancer (Brahmer J.R. et al., 2012; Topalian S.L. et al., 2012). Therefore, 
immunotherapy represents an attractive treatment strategy for R/M SCCHN, with promising 
preliminary data from studies involving immune checkpoint blockade. 
 
Clinical activity of pembrolizumab at 10mg/kg Q2W for treatment of recurrent/metastatic 
SCCHN in PD-L1 positive patients was demonstrated in the phase I Keynote-012 study 
(Seiwert T.Y. et al., 2016). 
 
In an initial cohort, the proportion of patients with ORR by central imaging review was 18% 
(8/45) in all patients and was 25% (4/16) in HPV-positive patients, whereas the ORR in HPV-
negative patients was 14% (4/29). In the full analysis set population (n=56) median progression-
free survival was 2 months, 4 months in the HPV-positive patients and 2 months in the HPV-
negative patients. Median overall survival (OS) was 13 months in the intention-to-treat 
population (n = 61), not reached for HPV-positive patients and 8 months for HPV-negative 
patients. 
 

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In an expansion cohort of the Keynote-012 study 132 patients with R/M SCCHN irrespective 
of PD-L1 expression or human papillomavirus (HPV) status received a fixed dose of 
pembrolizumab 200 mg administered every 3 weeks (Chow L.Q. et al., 2016). The ORR was 
18% (24/132) by central imaging review in biomarker-unselected patients. Similar to the initial 
SCCHN cohort of the Keynote-012 trial, a higher response to pembrolizumab was observed in 
HPV+ patients (32%, 9/28) versus HPV-negative patients (14%, 15/104). Of note, an ORR of 
14% was consistently observed in HPV-negative patients in both Keynote-012 cohorts. 
Treatment-related AEs of any grade occurred in 62% of patients, and treatment-related grade ≥ 
3 AEs occurred in 9% of patients. 
Based on the results of the Keynote-012 study, KEYTRUDA® (pembrolizumab) has been 
approved in the US in August 2016 at a fixed dose of 200 mg every three weeks for the treatment 
of patients with recurrent or metastatic SCCHN with disease progression on or after platinum-
containing chemotherapy and in EU in September 2018 for the treatment of recurrent or 
metastatic SCCHN in adults whose tumours express PD-L1 with a ≥ 50% TPS with disease 
progression on or after platinum-containing chemotherapy, based on the results from the phase 
III Keynote-040 (Cohen E.E.W. et al., 2019) with supportive data from Keynote-012 and 
Keynote-055. 
 
Another study, CheckMate-141 a Phase III, open-label, randomized study investigated 
nivolumab versus investigator’s choice of therapy in previously treated patients with SCCHN 
who have tumor progression on or within 6 months of platinum therapy in the primary, 
recurrent, or metastatic setting (Ferris R.L. et al.). The trial randomized 361 patients 2:1 to 
receive either nivolumab 3 mg/kg intravenously every two weeks or investigator’s choice 
(cetuximab/methotrexate/docetaxel) until documented disease progression or unacceptable 
toxicity. The study was stopped early after an independent monitoring panel determined the 
primary endpoint of improvement in OS was met with a median OS of 7.5 months (95%CI: 
5.5-9.1) for nivolumab and 5.1 months (95%CI: 4.0-6.0) for investigator’s choice of therapy 
(HR, 0.70; 97.73% CI, 0.51-0.96; P =0.01). The 1-year OS rates were 36% with nivolumab 
compared with 16.6% for investigator’s choice. The reponse rate was 13.3% in the nivolumab 
group versus 5.8% in the standard-therapy group (Ferris R.L. et al., 2016).  
 
Nivolumab has been approved in the US in November 2016 and in the EU in April 2017 for the 
treatment of patients with recurrent or metastatic SCCHN with disease progression on or after 
a platinum-based therapy, based on the results from CheckMate-141 (Ferris R.L. et al., 2016).  
 Rationale for the use of cancer vaccines in SCCHN 
 
At the present time there is no evidence to indicate that treatment should be different according 
to the HPV status. However, it is well recognized that HPV+ patients do well with a better 
progression-free survival and overall survival compared to HPV negative patients.  
The HPV status needs to be taken into account when designing all clinical trials for the 
treatment of oropharyngeal cancer, given the more favorable prognosis for HPV positive 
oropharyngeal cancer patients and the fact that this subset represents a distinct and well-defined 
entity. Testing patients with oropharyngeal cancer for HPV positivity is also useful prior to 
therapy given its prognostic implications, but there is insufficient information to alter therapy 
based upon HPV status. However, changes in the therapeutic approach to HPV positive 
oropharyngeal cancer can only be determined through prospective clinical trials and will need 
to be done carefully as to not compromise the excellent prognosis in these patients. 
 

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The structure of TG4001 should determine a higher efficacy specifically against HPV infected 
cells without any interaction with normal cells. 
 
TG4001 has been tested in a Phase II trial in HPV-16 associated cervical intraepithelial 
neoplasia (CIN) grade 2/3 demonstrating activity and higher efficacy compared to placebo in 
histologic resolution and response rates as well as viral clearance. Moreover the therapeutic 
vaccine/immunotherapeutic product was demonstrated to be safe with no major toxicities, apart 
from injection site reaction (Brun J.L. et al., 2011). 
 
 Rationale for combining TG4001 and immune checkpoints inhibitors 
 
Given the well-established role of immune system dysfunction in SCCHN, immunotherapy is 
an attractive treatment option, potentially associated with more tolerable side effects and 
improved efficacy. Recent advances in identifying SCCHN tumor antigens have provided 
targets for novel treatment modalities.  
 
The clinical and regulatory successes of the PD-1 and CTLA-4 checkpoint proteins are driving 
a resurgence of interest in immunotherapy as a mainstream form of cancer treatment, with 
numerous clinical studies exploring the application of these therapeutics in combination with 
traditional and experimental agents including therapeutic cancer vaccines and oncolytic virus 
immunotherapies (Melero I. et al., 2015).  
 
 Rationale for including other HPV-16 positive malignancies in the phase II of the 
study  
 
Appropriate treatment of incurable advanced disease for other HPV-16 positive cancers 
including cervical, anal, vulvar, vaginal and penile cancers consists mainly of platinum-based 
doublet chemotherapy which however has only limited efficacy in terms of response rate or 
median OS. Even though checkpoint blockade monotherapy has resulted in modest advances 
(Hollebecque A. et al., 2017), (Morris V.K. et al., 2017), (Frenel J.S. et al., 2017), (Ott P.A. et 
al., 2017), novel strategies of combining therapies are needed to improve the survival of 
recurrent and metastatic HPV-positive anogenital tract cancers.   
 
It is hypothesized that regardless the location of a HPV-16 positive tumor the presence of viral 
antigens leads to an induction of HPV-specific immune response which could augment the 
proportion of patients benefiting from PD-1 checkpoint blockade. 
 
 Rationale for the exclusion of oropharyngeal SCCHN in phase II part 2 
 
As outlined under section 1.1.8 KEYTRUDA® (pembrolizumab) has been approved in the US 
in August 2016 for the treatment of patients with recurrent or metastatic SCCHN with disease 
progression on or after platinum-containing chemotherapy and in EU in September 2018.   
In addition, OPDIVO® (nivolumab) has been approved in the US in November 2016 and in the 
EU in April 2017 for the treatment of patients with recurrent or metastatic SCCHN with disease 
progression on or after a platinum-based therapy in biomarker (PD-L1) unselected patients. 
 
This shift in standard of care has been observed during the conduct of the phase Ib and phase II 
part 1: while in phase Ib 5 out of 9 patients included had SCCHN, in phase II part 1 only 5 out 
of 32 patients included had SCCHN.     

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 Furthermore, with the registration of KEYTRUDA® in US and EU for first-line treatment of 
recurrent or metastatic SCCHN either as monotherapy or in combination with platinum and 5-
fluorouracil (5-FU) chemotherapy, the proportion of IO-naïve patients for second-line treatment 
will decrease significantly. As prior treatment with cancer immunotherapy is an exclusion 
criterion for this clinical study the number of eligible patients with SCCHN will be negligible.  
Therefore in order to be consistent with the current standard of care, patients with SCCHN will 
be excluded from the study population of the phase II part 2. 
 
 Rationale for transforming the phase II into a randomized, open-label controlled 
study 
 
At the time of interim analysis of phase II part 1 a pooled efficacy analysis was performed in a 
population of 34 evaluable patients consisting of 6 patients of the phase Ib treated with the 
recommended phase II dose of TG4001 and 28 evaluable patients included at cut off for the 
interim analysis. Out of these 34 patients, 15 presented anal cancer, 8 oropharyngeal cancer, 6 
cervical cancer and 5 vulvar/vaginal cancer. The ORR was 23.5% and the Disease Control Rate 
(DCR) at 12 weeks 41.2% representing a valuable anti-tumor activity in a population of patients 
with HPV-16+ pre-treated recurrent/metastatic (R/M) cancers and comparing positively to the 
ORR observed for avelumab alone. In a randomized trial evaluating avelumab alone or in 
combination with cetuximab in pretreated unresectable, locally advanced or metastatic 
squamous cell anal carcinoma, ORR was 10% (3/30) for avelumab alone vs 17% (5/30) for  
avelumab combined with cetuximab (Lonardi S. et al., 2020). In the Javelin phase I b cohort 
enrolling patients with platinum-refractory/ineligible R/M SCCHN, ORR was 13.1% in the 
overall population. A higher response to avelumab was observed in HPV+ patients (17.9%, 
7/39) versus HPV-negative patients (11.1%, 11/99, (Guigay J. et al., 19-21 September 2020).  
Considering other PD-L1 / PD-1 inhibitors, the largest clinical experience in HPV-related 
malignancies comes from KEYTRUDA® (pembrolizumab). As described under 1.3.2 in 
patients with R/M SCCHN with disease progression on or after platinum-containing 
chemotherapy unselected for biomarker, the ORR was 18% (24/132) by central imaging review 
and 20% by investigator review. A higher response to pembrolizumab was observed in HPV+ 
patients (32%, 9/28) versus HPV-negative patients (14%, 15/104, KEYNOTE-012 expansion 
cohort ). In SCCHN patients whose tumours express PD-L1 with a ≥ 50% TPS, the ORR was 
26.6% (KEYNOTE-040).  
The ORR of pembrolizumab was 12.2% (12/98) evaluated in patients with R/M cervical cancer 
with disease progression on or after platinum-containing chemotherapy unselected for 
biomarker (Chung H.C. et al., 2019). Based on these results pembrolizumab has been approved 
in PD-L1 positive cervix cancer in the US in 2018.  
In the pooled analysis of KEYNOTE-28 and KEYNOTE-158 evaluating pembrolizumab as 
monotherapy in patients with advanced anal squamous cell carcinoma the ORR to 
pembrolizumab was 10.9% (15/137) (Marabelle A. et al., 2020). 
It has been acknowledged that combining immune checkpoint blockade with a HPV-antigen 
targeting immunotherapy can represent a complementary immune strategy to increase the 
proportion of patients benefiting from checkpoint blockers and promising results have been 
published. In a single arm trial evaluating ISA101, a synthetic long peptide HPV-16 vaccine 
targeting E6 and E7, in combination with nivolumab in patients with advanced HPV-16+ 
tumors, an ORR of 33% (8/24) has been observed (Massarelli E. et al., 2019). MEDI0457, a 
DNA vaccine expressing HPV16/18 E6/E7 proteins and IL-12, was evaluated in combination 
with anti-PD-L1 durvalumab in patients with R/M HPV+ SCCHN. ORR was 22.2% (6/27) in 

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this study (Aggarwal C. et al., 2020).The ORR of 23.5% observed in our study is in line with 
these published results.  
The ultimate validation however whether adding a HPV vaccine to an anti-PD1/PD-L1 leads to 
an increase of the proportion of patients benefiting from checkpoint blockers needs to be done 
in a trial evaluating the combination of the vaccine with the anti-PD1/PD-L1 vs the anti-
PD1/PD-L1 alone. This randomized phase II trial will include patients with any HPV-16 
associated anogenital cancer stratified on the primary site (anal, cervix, genital).  
 
 Rationale for the restriction on the extent of liver metastases for eligibility in phase 
II part 2 
 
Out of the 34 patients for the pooled efficacy analysis, 15 presented anal cancer, 8 
oropharyngeal cancer, 6 cervical cancer and 5 vulvar/vaginal cancer. Median age was 61 years, 
the majority (88%) had received at least 1 prior line of chemotherapy (CT) with 32% having 
received ≥ 2 lines. 
8 patients achieved confirmed response according to RECIST 1.1 (1 CR, 7 PR, ORR 23.5%). 
Responses were observed in all primary tumor types and across all lines of prior therapy. 
Regarding the type of organs affected, there was a positive trend for lymph nodes; conversely 
the presence of liver metastases had a significant negative impact on outcome:  ORR was 0% 
and PFS 1.4 months in patients with liver metastases (n=11) versus 34.8% and PFS of 5.6 
months in patients without liver metastases (n=23).  
Out of the 11 patients with liver metastases at baseline, none of them had more than 3 liver 
metastases but 10 patients had a hepatic target disease greater than 30 mm. The single patient 
with hepatic target disease of 12.1 mm remained stable until week 12.  
It has been repeatedly described in the literature that liver metastasis at the time of diagnosis is 
associated with poor prognosis. Even though immunotherapy with the most successful 
candidates anti-PD-L1 or anti-PD-1 have shown clinical activity, however, their efficacy 
remains uncertain in patients with liver metastases. Different potential mechanisms are being 
proposed for this finding. When exploring the association between liver metastases, tumor 
CD8+ T-cell count and response to the anti-PD-1 pembrolizumab it turned out that presence of 
liver metastases was associated with fewer infiltrating CD8+ cells at the invasive margin in 
distant tumors, suggesting a systemic effect of the liver metastases (Tumeh P.C. et al., 2017).  
Therefore, and in order to balance between the assumption that patients with important hepatic 
disease will not benefit from an IO-based therapy and the need to seek optimal therapy for 
patients with limited hepatic disease, an eligibility criterion has been introduced limiting the 
number of liver metastases to a maximum of 3, with a maximum size in target disease to ≤ 30 
mm.   
 
 Summary of the overall benefit and risk 
 
 Expected benefits 
 
TG4001 is a human papillomavirus (HPV) targeted active immunotherapy product designed for 
the treatment of HPV-16 related diseases. TG4001 preclinical data demonstrated that TG4001 
has CD8+T cell dependent antitumor activity and confers immunity against TC1 tumors 
expressing wild-type HPV-16 E6 and E7 genes.  
 
The PD-1 pathway is a key mechanism by which many cancers evade immune surveillance. 
Immune checkpoints inhibitors have shown promising activity in SCCHN and anogenital tract 

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cancers like cervical or anal cancer. It is therefore, hypothesized that the combination of a 
checkpoint inhibitor with TG4001 may cause additional changes in the tumor 
microenvironment leading to enhanced anti-tumoral activity.  
 
 Potential risks 
 
With TG4001: 
Experimental data derived from murine models demonstrated an acceptable safety profile and 
no oncogenic potential. It was highlighted a slight to moderate irritant effects (erythema, and/or 
edema) at the injection site, decreased reticulocytes and lymphocytes, and an increased spleen 
weight that correlated with lymphoid hyperplasia (potential effect of exaggerated 
pharmacology). 
The following were the most common reported AEs in clinical trials (incidence >1%): 
- 
Injection site reaction 
- 
Injection site erythema 
- 
Pyrexia 
- 
Injection site pain 
- 
Injection site inflammation 
- 
Headache 
- 
Asthenia 
- 
Fatigue 
- 
Lymphadenopathy 
- 
Injection site oedema 
- 
Injection site induration 
- 
Nausea 
- 
Influenza like illness 
- 
Chills 
- 
Injection site pruritus 
- 
Injection site rash 
- 
Injection site haematoma 
- 
Injection site haemorrhage 
- 
Pain 
 
With avelumab: 
Specific risks associated with the use of avelumab as a monoclonal antibody have been 
observed. 
The risks of exposure to avelumab include mainly: 
• 
Severe infusion-related reactions (grade ≥3) including drug hypersensitivity reactions 
• 
Immune-related adverse reactions (immune-related pneumonitis, immune-related 
colitis, immune-related hepatitis, immune-related myocarditis, immune-related 
pancreatitis, immune-related endocrinopathies (thyroid disorders, adrenal insufficiency, 
new onset type I diabetes mellitus, pituitary disorders), immune-related nephritis and 
renal dysfunction and other immune-related AEs (myositis, Guillain-Barré syndrome, 
uveitis, and myasthenia gravis/myasthenic syndrome). Fatal outcome was reported for 
immune-related hepatitis, immune-related pneumonitis, immune-related myocarditis, 
and immune-related pancreatitis. 
 
The safety data from patients with different tumor types treated with avelumab in the clinical 
trials suggest an acceptable safety profile of the compound. Most of the observed events were 

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either in line with those expected in patients with advanced solid tumors or with similar class 
effects of MoAb blocking the PD-1/PD-L1 axis. Infusion-related reactions including drug 
hypersensitivity reactions and immune-mediated adverse reactions have been identified as 
important risks for avelumab.  
 Measures taken during the study to mitigate the risks 
 
The risk-benefit relationship has been carefully considered in the planning of the trial. Based 
on the pre-clinical and clinical data available to date on both IMPs, the conduct of the trial is 
considered justifiable using the dose(s) and dosage regimen(s) of TG4001 and the avelumab as 
specified in this clinical trial protocol.  
 
Respective risk mitigation measures as regard to the expected potential drug reaction to 
avelumab have been implemented in the current clinical study (see Section 6.5.2). In addition, 
a safety committee is planned for the ongoing assessment of the risk-benefit ratio. The trial 
shall be discontinued in the event of any new findings that indicate a relevant deterioration of 
the risk-benefit relationship and would render continuation of the trial unjustifiable. 
This clinical trial will be conducted in compliance with the clinical trial protocol, Good Clinical 
Practice (ICH Topic E6, Good Clinical Practice [GCP]) and the applicable national regulatory 
requirements. 
 
2 OBJECTIVES 
 
 Primary objective 
 
Phase Ib: To evaluate the safety and tolerability of the combination of TG4001 plus avelumab 
in patients with recurrent or metastatic HPV-16 positive advanced malignancies. 
 
Phase II part 1: To evaluate the efficacy of TG4001 combined to avelumab in terms of Overall 
Response Rate (ORR) by using RECIST 1.1 in patients with recurrent or metastatic (R/M) 
HPV-16 positive advanced malignancies including oropharyngeal SCCHN. 
 
Phase II part 2: To compare the PFS of TG4001 in combination with avelumab vs avelumab 
alone in patients with R/M HPV-16 positive advanced malignancies and without liver 
metastases at baseline. PFS will be evaluated based on RECIST 1.1. 
 
 Secondary objectives (Phase Ib + II) 
 
To evaluate the combination of TG4001 and avelumab with respect to: 
• Overall Response Rate (ORR) by using RECIST 1.1 (phase Ib and phase II part 2)   
• Progression Free Survival (PFS, phase Ib and phase II part 1)  
• Overall Survival (OS) 
• Duration of Response (DoR) 
• Disease control rate (DCR) 
• Safety profile (phase II)  
• Percentage of patients with liver metastases at baseline who have disease progression at 
D43 (phase II part 2) 
 

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 Exploratory objectives (phase Ib +II) 
 
- 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 STUDY DESIGN 
 
 Overall study design and plan description 
 
 Overall design and treatment plan 
 
This is a multicenter, open label phase Ib/II study evaluating the combination of TG4001 and 
avelumab in patients with HPV-16 positive advanced malignancies. 
The phase II consists of two parts: phase II part 1 is a single arm study (TG4001 with avelumab) 
and phase II part 2 is a randomized, controlled two arms study (TG4001 with avelumab vs 
avelumab alone). 
In the phase Ib: safety will be assessed in consecutive cohorts of 3 to 6 patients at increasing 
doses of TG4001 in combination with avelumab according to a 3+3 design (see table below). 
There will be no intra-patient dose escalation.  
Patients will receive TG4001 on a weekly basis on Days 1, 8, 15, 22, and 29, then every 2 weeks 
(starting on Day 36) until Month 6 (from Day 1 of study treatment), thereafter once every 12 
weeks, until disease progression, unacceptable toxicity, patient withdrawal from study for any 
reason or for a maximum of 2 years, whichever occurs first. Avelumab will be given once every 
2 weeks starting from Day 8 (one week after the first vaccine dose), until disease progression, 
unacceptable toxicity, patient withdrawal from study for any reason or for a maximum of 2 
years, whichever occurs first. 
Beyond 2 years of treatment and based on the clinical judgement of the investigator the patient 
could continue to receive study treatments according to the Study Flow-Chart (APPENDIX 
IIIB). 
 
Dose escalation (3+3 design) 
Two dose levels are planned for TG4001: doses of 5 x 106 PFU (DL1) and 5 x 107 PFU (DL2) 
in combination with avelumab at 10 mg/kg. Depending on the nature of the DLTs observed at 
these two DLs, alternative schedule for TG4001 (Q4W) may be tested with the combination. In 

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that case a minimum of 6 additional patients will be included. Implementation of this alternative 
schedule will be subject to a substantial amendment to this clinical study protocol. 
A minimum of 3 patients will be required at each dose level. If the maximal tolerated dose 
(MTD) is reached where 1 of 3 patients experiences a DLT, the cohort will be expanded with 3 
additional patients at the same DL (a maximum of 6 patients will be enrolled at each DL). 
 
Enrolment within a given cohort: The first patient will be monitored for 2 weeks (i.e. 7 days 
after the first administration of both products in combination) before the next two patients of 
the cohort can be enrolled simultaneously. In case the cohort must be extended by 3 additional 
patients for occurrence of a DLT among the first 3 treated patients, an interval of 2 weeks will 
be applied between the first additional patient and the 2 additional next patients.  
Enrolment into the next cohort: Enrolment into the next cohort cannot begin until the last patient 
in the previous cohort has completed her/his 4 weeks (from Day 1 to Day 28) of study treatment 
(interval time for assessment of DLT) or experienced a DLT. 
 
Number of DLTs / evaluable 
patients  
Rule 
0/3 
Accrue 3 new patients at the next dose level 
1/3 
≥ 2/3 
 
1/6 
Accrue 3 additional patients at current dose level 
Stop current dose = unacceptable dose 
MTD = dose immediately below 
Accrue 3 new patients at the next dose level 
≥ 2/6 
Stop: current dose = unacceptable dose 
MTD = dose immediately below 
The dose level at which unacceptable toxicity in at least 2/3 or 2/6 patients occurs will be considered as 
the unacceptable dose. The MTD will be considered as the dose immediately below. If no DLT  in more 
than 1/3 or 1/6  is observed, the MTD will be considered as the recommended dose for the phase II 
(RP2D).  
A total of 6 patients will be treated at the MTD. 
If at both Dose Levels no DLT in more than 1/3 or 1/6 patients is observed, the MAD, Maximum 
Administered Dose (DL2), will be considered as the recommended dose for the phase II 
(RP2D). 
Upon completion of phase Ib and for the purpose of clarification RP2D for TG4001 
corresponds to DL2, i.e. 5 x 107 PFU. 
 
In the phase II part 1, patients will be treated at the established RP2D for TG4001, i.e. 5 x 107 
PFU in combination with avelumab until disease progression, death or unacceptable toxicity, 
or study withdrawal for any reason, or for a maximum of 2 years, whichever occurs first. 
In the phase II part 2, patients will be treated at the established RP2D for TG4001, i.e. 5 x 107 
PFU in combination with avelumab 800 mg Q2W (combination arm) or with avelumab 800 mg 
Q2W alone (monotreatment arm) until disease progression, death or unacceptable toxicity, or 
study withdrawal for any reason, or for a maximum of 2 years, whichever occurs first. 
Beyond 2 years of treatment and based on the clinical judgement of the investigator the patient 
could continue to receive study treatments according to the Study Flow-Chart (APPENDIX 
IIIB and D). 
 

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In the phase II part 1, evaluation of efficacy and further evaluation of safety of the combination 
of TG4001 and avelumab will be performed in a single arm of patients with recurrent or 
metastatic HPV-16 positive advanced malignancies including HPV-16 positive oropharyngeal 
squamous cell carcinoma of the head and neck (SCCHN). 
 
In the phase II part 2, evaluation of efficacy of the combination of TG4001 and avelumab will 
be performed in a randomized, open-label controlled study comparing TG4001 in combination 
with avelumab (combination arm) to avelumab alone (monotreatment arm) in patients with 
HPV-16 positive recurrent or metastatic malignancies.  
• In patients without liver metastases at baseline randomization will be conducted equally 
in a 1:1 ratio TG4001 with avelumab (combination arm) versus avelumab alone 
(monotreatment arm). A stratification will be done on primary tumor site. 
• In patients with liver metastases at baseline randomization will be conducted equally in 
a 1:1 ratio TG4001 with avelumab versus avelumab alone, no stratification will be 
performed.  
 
In both phases, tumor response will be evaluated at baseline and then every 6 weeks until 
disease progression. Beyond 9 months after start of treatment, tumor evaluation will be 
performed every 12 weeks until disease progression. Tumor evaluations will be based on local 
assessment using RECIST 1.1. 
All patients will be followed up until disease progression or death due to any cause or the date 
of data cut-off, whichever occurs first. 
 
For all patients included in the phases Ib and II of the study, blood samples and tumor samples 
from biopsies will be collected for immunological tests and translational research. 
 
 
A schematic illustration of the trial design is shown in Figures 3-1 and 3-2 below. 
 

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Figure 3-1 :  Overall study design and investigational plan phase Ib and phase II part 1 
 
 
 

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Figure 3-2 :  Overall study design and investigational plan phase II part 2 
 
 

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 Number of centers and patients 
 
Phase Ib: a maximum of 12 evaluable patients depending on the safety of the combination, in 
3 centers  
Phase II part 1: at least 22 evaluable patients until the first stage of the Simon design in up to 
20 centers. 
Phase II part 2 in up to 25 centers:  
For patients without liver metastases a sample size of 50 patients (25 patients in each arm) is 
estimated to reach the number of PFS events required for Interim Analysis. Following Interim 
Analysis and sample size adjustment reviewed by the Independent Data Monitoring Committee 
(IDMC) a total of 120 patients are to be recruited until Q1 2024 to reach the number of PFS 
events required for Final Analysis. A 5% lost to follow-up or withdrawal of consent rate is 
estimated. With an actual recruitment rate of 2 patients per month, at least 80 patients will be 
recruited until Q1 2024. 
For patients with liver metastases a sample size of 
 is 
planned. 
 
 Independent Data Monitoring Committee 
 
An Independent Data Monitoring Committee (IDMC) will be set up during the study. In the 
phase Ib, the IDMC will be composed of 2 independent clinicians, external to the study.  
In the phase II part 2, the IDMC will be composed of 2 independent clinicians and 1 independent 
statistician. 
Representatives of Transgene (Medical monitor, Clinical Project Manager, Pharmacovigilance 
physician) and Merck KGaA / EMD Serono (Medical monitor) will be invited to all meetings 
for reporting of clinical data and to respond to any specific questions the IDMC may have on 
the conduct of the study. 
Additional study team members may attend if deemed necessary (Clinical trial manager, 
Statistician). If deemed appropriate, the coordinating investigator of the study and the study 
investigators of the concerned centers will be invited for cases requiring specific explanation. 
The Sponsor can appoint any additional independent expert if needed. 
 
A charter describing the responsibilities of the IDMC as well as the working procedures will be 
provided in a separate document. 
 
- 
In the phase Ib of the study: 
During the phase Ib of the study, the safety data of all enrolled and treated patients will be 
collected and evaluated by the Investigators, Transgene and Merck KGaA / EMD Serono on an 
ongoing basis. The IDMC will meet before each new cohort begins to analyze and review the 
safety data of all patients in the previous cohort. The IDMC will then recommend on 
continuation of accrual and whether it is possible to do the dose escalation as per the study 
design.  
At the end of the phase Ib and depending on the nature of the toxicities observed, the safety 
data of all patients will be analyzed and discussed with the IDMC which will make 
recommendation to the sponsor on the start of accrual in the phase II of the study. DLT 
evaluation is performed 4 weeks after the last patient enrolled in the phase Ib had first dose of 
study treatments. 
 
- 
In the phase II part 1 of the study: 

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During the phase II part 1 of the study the IDMC will review safety data at interim analysis. 
However, the IDMC may meet at any time on Sponsor request, especially in the case of 
unexpected toxicities or significant SAEs occurrence.  
 
- 
In the phase II part 2 of the study: 
During the phase II part 2 of the study and in addition to safety review the IDMC will evaluate 
efficacy results at interim analysis. 
 
 Patient accrual and duration of study 
 
This study is expected to start in Q3 2017 and is expected to be completed by Q4 2024. 
For safety reasons, inclusion of the patients in the phase Ib will be performed with a security 
interval of 2 weeks between the first patient of each cohort and the next 2 patients of the cohort. 
 
In case of no safety concerns and for the further conduct of the study it is understood that the 
accrual rate is based on reasonable planning expectations. The actual accrual rate should be 
compared to the expected rate on an ongoing basis. If problems with recruitment are 
encountered this should be discussed with Transgene as early as possible in order to institute 
measures to meet the above timelines. 
 
 Discussion of study design  
 
The study is designed as a phase Ib/II trial to evaluate the safety and efficacy of the combination 
of TG4001 with avelumab in patients with HPV-16 positive recurrent or metastatic cancer 
including oropharyngeal SCCHN patients. 
The phase II consists of two parts: the phase II part 1 is a single arm study (TG4001 with 
avelumab) and the phase II part 2 is a randomized, open-label, controlled two arms study 
(TG4001 with avelumab vs avelumab alone). 
TG4001 was studied in several clinical trials including patients with HPV-16 positive CIN2-3, 
HPV-16 positive cervical cancer and HPV-16 positive VIN3 at doses ranging from 5 x 105 PFU 
to 5 x 107 PFU administered by SC injections. The clinical data generated in CIN demonstrated 
that such HPV targeted active immunotherapy could eradicate HPV infected cervical cells by 
generating T-cell responses. In addition TG4001 displayed a good safety profile across all these 
studies (see Section 1.2.1). 
 
Taking into account the fact that TG4001 has not been investigated previously in combination 
with avelumab, the study will be run in its first phase Ib in cohorts of 3 to 6 patients using a 
traditional 3+3 design to test two doses of TG4001 (5 x 106 and 5 x 107 PFU) in combination 
with a fixed dose of avelumab (10 mg/kg) in order to evaluate the safety profile of the 
combination of the two agents. 
Should the data from this phase Ib of the study confirm the good tolerance of the combination, 
the study will be expanded (phase II of the study) to determine the efficacy of the combination 
in terms of overall response rate in this population of patients.  
 
The phase II part 1 of the study is designed as an open label, single arm study evaluating the 
efficacy of combination of TG4001 + avelumab. The primary efficacy endpoint for the phase 
II of the study is ORR, this endpoint is widely accepted as directly attributable to drug effect 
without necessity of a control arm. It is also considered as an early endpoint allowing decision 
making to continue clinical development of TG4001 in combination with checkpoint inhibitors. 

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The phase II part 2 of the study is designed as a randomized, open label, controlled two arms 
study comparing the PFS of TG4001 in combination with avelumab vs avelumab alone. 
For the cohort of patients without liver metastases at baseline, due to the uncertainty on the true 
treatment effect and data variability, and to reduce the risk of running an underpowered study, 
it is considered appropriate to adopt an adaptive approach to the sample. This will offer a 
mechanism to adjust the sample size to updated treatment effect and variability estimates seen 
at a planned interim analysis (Mehta C.R. and Pocock S.J., 2011). 
 
The hypothesis for median PFS in the combination arm (TG4001 with avelumab) is set at 4.5 
months and the hypothesis for median PFS in the monotreatment arm (avelumab alone) is set 
at 2.0 months. Interim analysis is performed after 37 PFS events and based on the conditional 
power observed, 120 patients should be enrolled to reach at Final Analysis a conditional power 
of 90% based on 104 PFS. To stick with initial timelines and with an observed enrollment of 
only 2 patients per month, Final Analysis will be performed based on at least 69 PFS events 
reaching a conditional power higher than 75% corresponding to at least 80 randomized patients. 
 Doses and schedule selection 
 
 TG4001 doses selection  
 
The doses of TG4001 for the Phase Ib of the study were selected based on an evaluation of the 
toxicology data, in-vivo efficacy in oncology models, and clinical data in patients with cancer 
treated with TG4001. TG4001 was demonstrated to be safe up to the highest dose of 5 x 107 
PFU in patients with gyneacological cancers. The starting dose chosen for TG4001 will be 5 x 
106 PFU, in case no DLT occurs in combination with avelumab 10 mg/kg, the dose of 5 x 107 
PFU used in previous clinical trials, which demonstrated to be safe will be tested in combination 
with avelumab 10 mg/kg. It is expected that the combination will be safe. Nevertheless, should 
DLTs or unexpected toxicities occur with the combination of TG4001 and avelumab, 
alternative dosing regimen of TG4001 and/or avelumab will be considered (See Section 3.1.1). 
 
 TG4001 schedule selection 
 
TG4001 previous clinical development in gynaecological conditions was conducted according 
to a standard immunization regimen of 3 injections weekly (Days 1, 8, 15). The large and most 
recent phase II study (study NV25025) showed TG4001 activity when compared with placebo 
in both histologic assessments and viral clearance, even though primary efficacy endpoint for 
the treatment response rate of at least 60% was not achieved. One hypothesis that may explain 
a lower than expected response rate is that additional administrations were needed. Indeed, 
other large randomised phase II studies with MVA-based products developed by Transgene [i.e. 
TG4010 (MVA-MUC1-IL2) and TG4040 (MVA-HCV)] completed positively with schedules 
of immunization characterized by more administrations (weekly for 6 weeks followed by 
repeated boost of vaccination at regular interval). 
 
Both animal toxicology data from TG4001 and similar viral vectored products (TG4040 and 
TG4010) demonstrated an acceptable safety profile of MVA-based products. The dose, the total 
number of injections and the intended treatment period in the proposed study with TG4001 
were tested with either TG4001 or a similar construct in 3 animal species as shown in Table 3-
1 below. None of these studies evidenced toxic findings up to 20 injections for 5 months other 
than inflammation at the injection site.  

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Table 3-1 : Summary of toxicology data supportive of the intended treatment regimen 
Study 
Number of injections 
Treatment duration 
Highest dose 
TG4001 / Rat 
8 
1 month 
6x106 PFU 
TG4001 / Mice 
4 
1 month 
4x107 PFU 
TG4001 / Rabbit 
3 
1 month 
5x106 PFU 
TG4010 / Mice 
9 
3 months 
4x107 PFU 
TG4040 / Rabbit 
20 
5 months 
1x108 PFU 
 
The good tolerance in animals was further confirmed in patients. Previous human experience 
with TG4001 and similar products is summarized in Table 3-2. After iterative injections with 
MVA-based products for several months in cancer patients or chronic hepatitis C patients, the 
safety profile of the recombinant vector was satisfactory; the adverse events were mainly 
associated to the disease or the concomitant treatment. 
 
Table 3-2 : Previous human experience with TG4001 and similar MVA-based products 
Product 
Number of 
treated 
patients* 
Max number of injections 
Highest 
dose 
(PFU) 
Summary of adverse drug 
reactions 
TG4001 
(MVA-HPV-
IL2) 
313 
3 
(weekly) 
5x107 
injection site reactions, 
including erythema, pain, or 
reaction not otherwise specified 
TG4010 
(MVA-MUC1-
IL2) 
380 
51 
(weekly for the first 6 
weeks then every 3 weeks 
up to progression) 
1x108 
fatigue, injection site reactions, 
erythema 
TG4040 
(MVA-HCV) 
173 
13 
(weekly) 
1x108 
injection site reactions, fatigue, 
flu-like symptoms, headache 
*as of December 2016 
 
Based on the safety review from available animal and clinical studies conducted with our MVA-
based products injected dozens of times per individual, there is no known toxicity after multiple 
administrations of MVA viruses. Thus, the company believes that the dose regimen of TG4001 
in the proposed study is safe.  
 
Therapeutic vaccines do not directly target the tumor but they rather aim to activate and amplify 
the immune reactions against the tumor. Immune responses often take time to develop and can 
potentially be enhanced by continued booster vaccinations. Therefore, the proposed schedule 
of administration of TG4001 in co-administration with avelumab in the present study uses 
weekly SC injections of TG4001 on Days 1, 8, 15, 22, and 29 of study treatment, then once 
every 2 weeks (starting on Day 36) up to Month 6, thereafter once every 12 weeks up to Month 
24, fitting with the schedules of administration of the two other MVA based products and with 
the schedule of visits at the hospital.  
 
 Avelumab dose selection  
 

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The avelumab dose of 10 mg/kg was selected after review of the PK, pharmacodynamics, 
receptor occupancy, and preliminary clinical safety and efficacy data observed in the ongoing 
Phase I to III monotherapy studies of over 1700 subjects that have received this dose. 
For the phase II part 2 avelumab will be administered at 800 mg flat dose every 2 weeks at the 
same schedule as in phase Ib and phase II part 1. This dose regimen has been approved in global 
markets. Avelumab was originally dosed on a mg/kg basis to reduce inter subject variability in 
drug exposure. However, data for mAbs, including the marketed PD-1 and PD-L1 ICIs 
inhibitors nivolumab, pembrolizumab and atezolizumab, reveal that body weight based dose 
regimens do not result in less variability in measures of exposure over fixed (i.e., body weight 
independent) dose regimens (Wang D.D. et al., 2009), (Freshwater T. et al., 2017), (Zhao X. et 
al., 2017). Simulation showed that exposures to avelumab across the available range of body 
weights are less variable with 800 mg every 2 weeks compared with 10 mg/kg every 2 weeks; 
exposures were similar near the population median weight. Furthermore, the 800 mg every 2 
weeks dose regimen is expected to result in Ctrough > 1 mg/mL required to maintain avelumab 
serum concentrations at > 95% TO throughout the entire every 2 weeks dosing interval in all 
weight categories. Furthermore, the advantages of flat dosing are minimizing drug wastage, 
facilitating preparation and administration, and reducing pharmacy errors (Wang D.D. et al., 
2009). 
4 STUDY POPULATION 
 
 Inclusion criteria 
 
Patients must satisfy all the following inclusion criteria for entry into the study 
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 (for phase II part 2: part of normal patient care can be: e.g. CT or MRI, biopsy, 
determination of HPV-16 positivity by specified central laboratory) 
2. Female or male patients, aged at least 18 years (no upper limit of age for phase Ib and 
phase II part 1), 18 to 80 years of age (for phase II part 2) 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 (Appendix 
I) 
4. Life expectancy of at least 3 months 
5. Patients 
with 
histologically 
or 
cytologically 
documented 
metastatic 
or 
refractory/recurrent HPV-16+ cancer (determined in an accredited central laboratory 
using a validated assay) 
6. Phase Ib and Phase II part 1: Patients with HPV-16 + cancers including oropharyngeal 
squamous cell carcinoma of the head and neck (SCCHN), cervical, vulvar, vaginal, 
penile, and anal cancer 
Phase II part 2: Patients with HPV-16 + cancers including cervical, vulvar, vaginal, 
penile, and anal cancer 
7. Disease MUST not be amenable to curative surgery resection or curative radiotherapy 
with documented disease progression after concertation with multidisciplinary board 
8. Prior therapy: 
Phase Ib and Phase II part 1: 
- 
Patients MAY have received up to two prior lines of systemic chemotherapy for the 
management of metastatic or recurrent disease; for SCCHN, patients MUST have 
previously been exposed to platinum-based therapy, either as part of definitive 
chemo-radiation OR as first line systemic treatment for metastatic disease which 

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may include cetuximab. Patients with recurrence/progression within 6 months of 
prior multimodal therapy using platinum-based therapy are eligible. Patients with 
cervical cancer may have undergone surgery and/or received definitive radiation or 
chemo-radiation therapy for localized disease. Patients MUST have been exposed 
to platinum–based chemotherapy for metastatic disease which may include 
bevacizumab. Patients with platinum-refractory disease will be eligible 
Phase II part 2: 
- 
For recurrent/metastatic disease no more than one prior line of chemotherapy which 
can contain a platinum 
- 
Prior treatment for metastatic disease is not required for:  
o Patients with recurrence/progression within 6 months after completion of prior 
multimodal therapy for localized or locally advanced disease not amenable to 
curative treatment   
o Patients who are unsuitable for platinum-based therapy  
o Patients who refuse chemotherapy or other standard therapies for the treatment 
of metastatic or recurrent disease. The benefit of an immunotherapy over 
standard therapies must be validated by the medical board and duly documented. 
A minimum of 4 weeks interval should have elapsed between the completion of the last  
chemotherapy and study treatment start 
    A minimum of 4 weeks interval between palliative bone directed radiotherapy and the     
    start of study treatment provided that radiation therapy does not affect the unique  
    measurable lesion, if applicable 
9. Phase II part 2: For patients with hepatic metastases: 
- 
no more than 3 hepatic lesions in total (target and non-target lesions) 
- 
maximum size of hepatic target disease ≤ 30 mm according to RECIST 1.1 
10. Phase Ib and phase II part 1: Availability of tumor tissue from biopsy: at least two 
fresh tumor tissue samples are to be collected. Tumor tissue may come either from the 
local tumor or distant metastasis. Cytological material is not accepted for this analysis 
Phase II part 2: 
- Availability of archived or fresh tumor tissue for the determination of HPV-16 
positivity.  
- . Patients must agree to undergo a core or excisional biopsy of a tumor lesion not 
previously irradiated (at least 2 fresh tissue samples to be collected). An archival 
sample obtained within one year prior to randomization is acceptable only if tumor is 
not accessible. Tumor tissue may come either from the local tumor or distant 
metastasis. Fine needle aspirates and bone biopsies are not adequate.  
11. At least one measurable lesion by CT scan according to RECIST 1.1. Tumors within a 
previously irradiated field will be designated as "non-target" lesions unless progression 
is documented or a biopsy is obtained to confirm persistence at least 90 days following 
completion of radiation therapy 
12. Adequate hematological, hepatic and renal function: 
- 
Hemoglobin  9.0 g/dL (for phase II part 2: without packed red blood cell 
transfusion within the prior 3 weeks) 
- 
Neutrophils  1.5x109/L 
- 
Total lymphocytes count  0.4x109/L 
- 
CD4 + ≥ 200 /µL 
- 
Platelets count  100x109/L 
- 
Total bilirubin ≤ 1.5 x ULN 

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- 
Serum 
transaminases 
(alanine 
aminotransferase 
[ALT] 
and 
aspartate 
aminotransferase [AST])  3 x ULN  
- 
Glomerular Filtration Rate  50 mL/min (according to Modification of the Diet in 
Renal Disease (MDRD) formula or Cockroft & Gault formula) 
- 
Serum albumin ≥ 30 g/L 
13. Negative blood pregnancy test at screening for women of childbearing potential 
(Appendix II) 
14. Highly effective contraception (i.e., methods with a failure rate of less than 1% per 
year) during the study period and for 3 months after the last study treatment 
administration for female patients of childbearing potential (WOCBP) and for male 
patients who are sexually active with WOCBP (See Appendix II for WOCBP definition 
and details on highly effective contraception methods). Highly effective contraception 
methods are defined as: 
• 
Hormonal methods of contraception including combined oral contraceptive 
pills, vaginal ring, injectables, implants, intrauterine devices (IUDs) such as 
Mirena and Nonhormonal IUDs such as ParaGard for WOCBP patient or male 
patient’s WOCBP partner  
• 
Tubal ligation  
• 
Vasectomy 
In addition to highly effective contraception, participating male patients  
• 
must use a condom during the study period and for 3 months after the last study 
treatment administration when engaging in any activity that allows for exposure 
to ejaculate 
• 
must refrain from donating sperm 
 
 Exclusion criteria 
 
If any of the following criteria apply, the patient must not enter into the study 
1. Prior exposure to cancer immunotherapy including cancer vaccines, any antibody/drug 
targeting T cell co-regulatory proteins (immune checkpoints) such as anti-PD-L1, anti-PD-
1, or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody 
2. a) Concurrent anticancer treatment within 28 days before the start of study treatment (e.g., 
chemotherapy, radiotherapy or cytokine therapy except erythropoietin) 
b) Recurrent drainage procedures (once monthly or more frequently) for pleural effusion, 
pericardial effusion, or ascites  
3. Major surgery within 28 days before the start of study treatment  
4. 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 the first study treatment, 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 
5. Patients with central nervous system (CNS) metastases except those meeting the following 
criteria: 
- 
Brain metastases that have been treated locally and are clinically stable during 4 weeks 
prior to start of study treatment 
- 
No ongoing neurological symptoms that are related to the brain localization of the 
disease (sequelae that are a consequence of the treatment of the brain metastases are 
acceptable) 

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6. Other active malignancy requiring concurrent systemic intervention  
7. Patients with previous malignancies other than the target malignancy to be investigated in 
this trial (except non-melanoma skin cancers, and the following in situ cancers: bladder, 
gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a 
complete remission was achieved at least 2 years prior to study entry AND no additional 
therapy is required during the study period 
8. Patient with any organ transplantation, including allogeneic stem cell transplantation 
9. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTC 
V4.03 or V5.0 for phase II part 2), any history of anaphylaxis, or uncontrolled asthma  
10. Any known allergy or reaction to eggs, gentamycin or attributed to compounds of similar 
chemical or biological composition to therapeutic vaccines/immunotherapeutic products 
11. Any known allergy or reaction to any component of anti-PD-1/PD-L1 or its excipients  
12. Patients with history of interstitial lung disease (phase Ib and phase II part 1) 
13. Patients with known history or any evidence of active interstitial lung disease / pneumonitis 
(phase II part 2) 
14. Administration of a live vaccine within 28 days prior to start of study treatment  
15. Participation in a clinical study with an investigational product within 4 weeks prior to the 
start of the study treatment 
16. Patients with active, known, or suspected auto-immune disease or immunodeficiency, 
except type I diabetes mellitus, hypothyroidism only requiring hormone replacement or skin 
disorders (such as vitiligo, psoriasis) not requiring systemic treatment 
17. Significant chronic or acute infections including infection with mpox and SARS-CoV-2 
(COVID-19) PCR positive testing 
18. Positive serology for Human Immunodeficiency Virus (HIV) or Hepatitis C Virus (HCV) 
or presence in the serum of the Hepatitis B surface antigens (HBsAg), at Baseline 
19. Persisting toxicity related to prior therapy of Grade ≥ 2 NCI-CTCAE v4.03 or v5.0 for phase 
II part 2 (except neuropathy [see exclusion criterion below] and alopecia). 
20. Neuropathy ≥ Grade 3 
21. Clinically significant (that is, active) cardiovascular disease: cerebral vascular 
accident/stroke or myocardial infarction (< 6 months prior to enrollment), unstable angina 
pectoris, congestive heart failure (New York Heart Association Classification Class ≥ II), 
or serious uncontrolled cardiac arrhythmia requiring medication/active intervention, history 
of myocarditis (history of myocarditis for phase II part 2). 
22. Patient with any underlying medical condition that the treating physician considers might 
be aggravated by treatment or might impair the patient’s tolerance to study treatment  
23. History of uncontrolled intercurrent illness including but not limited to: 
- 
Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mmHg or 
lower) 
- 
Uncontrolled diabetes (e.g., hemoglobin A1c ≥ 8%) 
- 
Uncontrolled infection (phase II part 2) 
24. Patients with pulse oximetry of less than 92% on room air (phase II part 2) 
25. Any psychological, familiar, sociological or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule; those conditions should be 
discussed with the patient before registration in the trial 
26. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test (> 10 mIU/mL) 
 

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 Criteria for patient premature withdrawal and replacement 
 
 Premature withdrawal from the trial 
 
Patients are free to discontinue the trial at any time without giving reasons. Withdrawal of 
consent will be considered withdrawal from the trial unless the patients agree to be followed 
until documentation of progressive disease, if applicable and for survival, which may include 
verification of medical records. 
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 treatment duration of this trial.  
 
In case of premature withdrawal from the trial, the investigations scheduled for the end of 
treatment visit should be performed (see Section 6.8), if possible, with focus on the most 
relevant assessments. In any case, the appropriate case report form (eCRF) section must be 
completed. 
 
 Withdrawal from the Investigational Medicinal Products 
 
Patients may discontinue the IMPs treatment (i.e., for another reason than documented disease 
progression according to RECIST 1.1 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 or significant worsening of existing 
symptoms. However, every effort should be made to document objective progression even 
after discontinuation of treatment 
- 
Adverse event(s) that according to the Investigator’s evaluation unacceptably endanger the 
safety of the patient 
- 
Physician’s determination that patient’s further participation in the study is not in the 
patient’s best interest 
- 
Patient’s request at any time for any reason (patient’s consent withdrawal) 
- 
Protocol violation 
- 
Lost to follow up 
 
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 progressive disease. 
If the reason for 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 visits. 
 
 Replacement policy 
 
In the phase Ib of the trial, only patients who do not complete the DLT observation period (the 
first 4 weeks of study treatment) for reasons other than a DLT or who are not evaluable for 
phase Ib safety analysis will be replaced. Patients who require discontinuation of TG4001 
and/or avelumab due to a DLT will not be replaced. An evaluable patient must have received 
at least one dose of both IMPs (TG4001 + avelumab) and have had at least one valid post-

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baseline safety assessment. The statement that a patient had no AE, on the Adverse Events 
eCRF page, constitutes a valid safety assessment. The occurrence of death also constitutes a 
valid safety assessment. 
In the phase II part 1 of the trial, whatever the reason for withdrawal, except for disease 
progression and death due to underlying cancer before scheduled scan 6 weeks after study 
treatment start could be performed, patients considered as non-evaluable for tumor response 
will be replaced. 
In the phase II part 2 of the trial, patients will not be replaced. 
 
 Definition of End of Study (EOS) 
 
The end of the trial will be defined as the date of last patient last visit (LPLV). 
 
5 INVESTIGATIONAL MEDICINAL PRODUCTS (IMPs) 
 
In this study the IMPs are TG4001 and avelumab. 
  
 TG4001  
 
TG4001 is a suspension of a recombinant attenuated Modified Vaccinia virus of Ankara 
(MVA strain), a significantly attenuated strain of Vaccinia virus, containing DNA sequences 
coding for the mutation-inactivated HPV-16 E6 and E7 antigens and for human Interleukin-
2. For further information see TG4001 Investigator’s Brochure.  
 
 
 
 
 
 
 
 
 
 
 
 
 
In this study, the formulation medium is also used as diluent for reconstitution to obtain the 
dose of 5 x 106 PFU (DL1). The product code of the diluent is TG0008. 
 
TG4001 and TG0008 will be supplied along with a Technical Sheet detailing their 
characteristics.  
 
 Packaging and labeling 
 
TG4001 is supplied as a frozen suspension filled in individual 4-mL glass vials (Type I glass). 
Each vial is intended for single use (i.e., 1 injection to 1 patient). The recoverable volume of 
TG4001 in each vial is 0.5 mL with an infectious titer of 5 x 107 PFU. TG4001 is a colorless to 
whitish liquid clear or slightly turbid at room temperature (see TG4001 Investigator’s Brochure 
and Technical Sheet). 
 
TG0008 is supplied as a frozen solution filled in individual 4-mL glass vials (Type I glass). 
Each vial is intended for single use. The recoverable volume of TG0008 in each vial is 0.5 mL. 
TG0008 is a sterile, colorless, preservative-free suspension for injection. 
 
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. 

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Packaging for shipment of TG4001 and TG0008 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 3373 regulations). TG4001 
and TG0008 are shipped on dry-ice with the official transport designation “Biological 
Substance, Category B”. Shipments are monitored with temperature control devices. 
 
 Conditions of storage and use 
 
TG4001 and TG0008 must be stored at -20°C +/-5°C (between -15°C and -25°C) in a freezer 
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. 
 
TG4001 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 a Technical Sheet and a Preparation Procedure that are provided by Transgene detailing 
instructions for TG4001 handling (biosafety requirements, preparation, administration, 
destruction) and incident management. 
 
During all TG4001 and TG0008 handlings, lab coat, goggles, gloves and mask must be worn. 
All transport of TG4001 and TG0008 (vial or syringe containing the dose to be injected) must 
be done using a leakproof container/bag. 
 
 Preparation for administration 
 
TG4001 doses will be prepared and handled according to the instructions provided in the 
Preparation Procedure provided by Transgene. TG4001 will be diluted in the diluent TG0008 
to obtain the dose of 5 x 106 PFU (DL1). No dilution will be necessary for the dose of 5 x 
107 PFU (DL2) since it is contained in the TG4001 vials. 
Upon completion of phase Ib and for the purpose of clarification RP2D for TG4001 
corresponds to DL2, i.e. 5 x 107 PFU. 
 
TG4001 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 TG4001 solutions.  
 
In case of incident while handling TG4001, the actions recommended are described in the 
Technical Sheet. Any incident must be documented by a written report to be sent immediately 
upon occurrence or knowledge to Transgene Medical Department or its designee: 
 
 
 
 
 
                                                       
 
 
 
 Disposal and destruction or return 
 
During the course of the study based on Transgene’s request and at termination of the study all 
unused TG4001 and TG0008 will be destroyed locally or returned to the supply provider 
contracted by Transgene. 

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For local destruction, the Investigator / Pharmacist or delegated person will ensure that 
destruction is performed according to written instructions for disposal of TG4001 (and 
TG0008) and waste generated during the TG4001 preparation and administration available in 
the TG4001 Investigator’s Brochure and the Technical Sheet, and will not expose humans to 
any risks from TG4001. A certificate of destruction will be completed and provided to 
Transgene (copy retained by the site). 
 
Alternatively, unused TG4001 and TG0008 may be returned to the supply provider contracted 
by Transgene with the appropriate documentation. The supply provider will coordinate the 
return of unused TG4001 and TG0008. A certificate of return will be completed and provided 
to the supply provider (copy retained by the site). 
 
Upon completion or termination of the study at a site, the monitor will verify that all used 
TG4001 and TG0008 vials have been destroyed, all unused TG4001 and TG0008 vials have 
been returned or destroyed, and no TG4001 or TG0008 vial remains on site. 
 
Accurate records of TG4001 and TG0008 received at, dispensed from, returned to and disposal 
of by the study site should be recorded appropriately on the drug log. 
 
 Supplier 
 
TG4001 and TG0008 will be supplied by or on behalf of Transgene for this study at no cost to 
the study participant. 
 
 Avelumab 
 
The active pharmaceutical ingredient in avelumab drug product is a fully human antibody of 
the immunoglobulin G (IgG) 1 isotype that specifically targets and blocks PD-L1, the ligand of 
PD-1. For further information see avelumab Investigator’s Brochure. 
 
 Packaging and labeling 
 
Avelumab is a sterile, clear and colorless concentrate for solution intended for intravenous (IV) 
administration. The drug is presented at a concentration of 20 mg/mL in Type I glass vial closed 
with a rubber stopper and sealed with an aluminium polypropylene flip-off seal. Each vial is 
intended for single use (i.e., 1 injection to 1 patient). 
 
Each vial contains 200 mg of avelumab as a preservative free-acetate buffered solution (pH 5.2) 
containing Mannitol and Polysorbate 20 (Tween 20).  
 
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. 
 
Avelumab is shipped in suitable transport containers according to its storage and shipping 
conditions. Shipments are monitored with temperature control devices. 
 

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 Conditions of storage and use 
 
Avelumab must be stored at 2°C to 8°C in a fridge until use under the supervision of the study 
Pharmacist / Investigator (or his/her delegate). Avelumab must not be frozen.  
 
Avelumab stored at room temperature (23°C to 27°C) or at elevated temperatures (38°C to 
42°C) for extended periods is subject to degradation. Rough shaking of avelumab must be 
avoided.  
 
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. 
 
For further information on avelumab storage and handling see avelumab Investigator’s 
Brochure. 
 
 Preparation for administration 
 
For administration in clinical trials, avelumab must be diluted with 0.9% saline solution 
(sodium chloride injection), supplied in an infusion bag, alternatively a 0.45% saline solution 
can be used if needed. Detailed information on infusion bags and medical devices to be used 
for the preparation of the dilutions and subsequent administration will be provided in the 
Manual of Preparation. 
 
The chemical and physical in-use stability for the infusion solution of avelumab in 0.45% or 
0.9% saline solution has been demonstrated for a total of 24 hours at room temperature. 
However, from a microbiological point of view, the diluted solution should be used 
immediately and is not intended to be stored unless dilution has taken place in controlled and 
validated aseptic conditions. It is consequently recommended that the diluted solution of 
avelumab is used immediately. 
 
No other drugs should be added to the solution for infusion containing avelumab. 
For further information on avelumab preparation see the Manual of Preparation. 
 
 Disposal and destruction or return 
 
During the course of the study based on Transgene’s request and at termination of the study all 
unused avelumab will be destroyed locally or returned to the supply provider contracted by 
Transgene. 
 
For local destruction, the Investigator / Pharmacist or delegated person will ensure that 
destruction is performed according to written instructions for disposal of avelumab and waste 
generated during the avelumab preparation and administration, and will not expose humans to 
any risks from avelumab. Any unused portion of the solution or unused vial should be discarded 
in biohazard waste disposal with final disposal by accepted local and national standards of 
incineration. A certificate of destruction will be completed and provided to Transgene (copy 
retained by the site). 
 
Alternatively, unused avelumab may be returned to the supply provider contracted by 
Transgene with the appropriate documentation. The supply provider will coordinate the return 

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of unused avelumab. A certificate of return will be completed and provided to the drug supply 
provider (copy remained by the site). 
 
Upon completion or termination of the study at a site, the monitor will verify that all used 
avelumab vials have been destroyed, all unused avelumab vials have been returned or 
destroyed, and no avelumab vial remains on site. 
 
Accurate records of avelumab received at, dispensed from, returned to and disposal of by the 
study site should be recorded appropriately on the drug log.  
 
 Supplier 
 
Avelumab will be supplied by or on behalf of Merck KGaA for this study at no cost to the study 
participant. 
 
6 TREATMENT PLAN 
 
 Trial medication administrations  
 
The study treatments for all patients in the phase Ib and the phase II part 1 of the study are 
TG4001 with avelumab. 
For the phase II part 2, study treatments are TG4001 with avelumab in the combination arm 
and avelumab alone in the monotreatment arm. 
 
The study drugs treatment will be given on an outpatient setting, where all facilities for 
observation of the patients during and after study drug administrations are available and are in 
accordance with the local regulations laws.  
 
 TG4001 
 
6.1.1.1.Administration of TG4001 
 
Phase Ib, phase II part 1 and phase II part 2 combination arm: TG4001 will be administered 
weekly on Days 1, 8, 15, 22, and 29, and then once every 2 weeks (starting on Day 36) up to 
Month 6 (D204), then once every 12 weeks for a maximum of 2 years or until disease 
progression or unacceptable toxicity, or premature discontinuation due to any reason, 
whichever occurs first. 
Beyond 2 years of treatment and based on the clinical judgement of the investigator the patient 
could continue to receive study treatments according to the Study Flow-Chart (APPENDIX 
IIIB and D). When both drugs are administered in the same day, TG4001 will be administered 
first (BEFORE avelumab) 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. 

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Inj. 1 in Left Thigh 
----> Inj. 2 in Right Arm 
  
 
 
 
Inj. 5  
 
    Inj. 6 
 
 
 
  
  
 
 
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.  
 
6.1.1.2.TG4001 dose administered and dose escalation scheme 
 
• In the phase Ib of the study 
Two dose levels will be tested: doses of 5 x 106 PFU (DL1) and 5 x 107 PFU (DL2) in 
combination with avelumab at 10 mg/kg tested in a 3+3 design (see Table 6-1).  
Depending on the nature of the DLTs observed at these two DLs, alternative schedule for 
TG4001 (Q4W) may be tested with the combination. In that case a minimum of 6 additional 
patients will be included. Implementation of this alternative schedule will be subject to a 
substantial amendment to this clinical study protocol. 
 
 
 
 
Table 6-1: Doses of TG4001 and avelumab in the phase Ib of the study 
Dose level 
TG4001 dose 
Avelumab dose  
Number of patients 
DL1 
5 x 106 PFU  
10 mg/kg  
3 – 6 
DL2 
5 x 107 PFU 
10 mg/kg 
3 – 6 
Dose escalation rules and definition of MTD 
All patients in the first DL (5 x 106 PFU) must complete the first 4 weeks treatment before dose 
escalation to the next dose level (DL2) will occur.  
There will be no intra-patient dose escalation; each patient will stay on the dose level assigned 
in the trial unless study drugs need to be stopped. 
Patients who experience a DLT will be withdrawn from the study treatment and followed up to 
disease progression or death, whichever occurs first. 
Patients who are not evaluable for DLT or who are withdrawn during the first 4 weeks of study 
treatment for other reasons than a DLT, will be replaced. 
 
Doses are escalated until MTD is reached as follows. 
Number of DLTs / evaluable 
patients  
Rule 
0/3 
Accrue 3 new patients at the next dose level 
1/3 
≥ 2/3 
 
Accrue 3 additional patients at current dose level 
Stop current dose = unacceptable dose 
MTD = dose immediately below 

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1/6 
Accrue 3 new patients at the next dose level 
≥ 2/6 
Stop: current dose = unacceptable dose 
MTD = dose immediately below 
 
The dose level at which unacceptable toxicity in at least 2/3 or 2/6 patients occurs will be 
considered as the unacceptable dose. The MTD will be considered as the dose immediately 
below. If no DLT in more than 1/3 or 1/6 is observed, the MTD will be considered as the 
recommended dose for the phase II (RP2D).  
A total of 6 patients will be treated at the MTD. 
If at both Dose Levels no DLT in more than 1/3 or 1/6 patients is observed, the MAD (DL2) 
will be considered as the recommended dose for the phase II (RP2D). 
 
Upon completion of phase Ib and for the purpose of clarification RP2D for TG4001 corresponds 
to DL2, i.e. 5 x 107 PFU. 
 
Dose limiting toxicity (DLT) will be assessed in each included and treated patient during the 
first 4 weeks [Day 1 to Day 28] of dosing (4 injections of TG4001 and 2 injections of avelumab) 
and includes the following toxicities: 
- 
Grade ≥ 3 drug related adverse event. However, fatigue, nausea/vomiting adequately 
treated with anti-emetics, endocrinopathies adequately controlled with one 
physiologic hormone replacement, skin toxicity and single laboratory values out of 
normal range without any clinical correlate, asymptomatic grade ≥3 lipase or 
amylase elevation, tumor flare defined as local pain, irritation, or rash localized at 
sites of known or suspected tumor or a transient Grade 3 infusion adverse event are 
excluded. 
- 
Liver function test abnormality:  
o AST or ALT > 5 x ULN  
o Total bilirubin > 3 x ULN 
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
- 
Drug related adverse event requiring treatment interruption for more than 2 weeks 
 
Toxicities will be graded according to National Cancer Institute’s Common Toxicity Criteria 
for Adverse Events (NCI-CTCAE), version 4.03. 
 
All adverse events that meet DLT criteria must be reported to Transgene, within 24 hours (See 
Section 9.4). 
 
• In the phase II part 1 and phase II part 2 combination arm 
TG4001 will be administered at the RP2D established during the phase Ib of the study in 
combination with avelumab. 
 
Upon completion of phase Ib and for the purpose of clarification RP2D for TG4001 
corresponds to DL2, i.e. 5 x 107 PFU. 
 
 Avelumab 
 
• In the phase Ib and phase II part 1 

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Avelumab will be administered at the dosage of 10 mg/kg as an IV infusion over 1 hour [-10 
minutes / +20 minutes, i.e., 50 to 80 minutes] once every 2 weeks. The dose of avelumab will 
be calculated based on the weight of the patient determined within 72 hours prior to the day of 
drug administration.  The dose of avelumab used for the previous administration can be repeated 
if the change in the patient’s weight is 10% or less than the weight used for the last dose 
calculation. 
Patients will be treated with avelumab once every 2 weeks, starting one week after the first 
vaccine dose (on Day 8), until disease progression, unacceptable toxicity, patient withdrawal 
from the study for any reason, or for a maximum of 2 years, whichever occurs first. 
Beyond 2 years of treatment and based on the clinical judgement of the investigator the patient 
could continue to receive study treatments according to the Study Flow-Chart (APPENDIX 
IIIB).  
In order to mitigate infusion-related reactions, subjects will receive pretreatment with histamine 
H1 receptor blockers and acetaminophen/paracetamol 30 to 60 minutes prior to every avelumab 
infusion. A premedication regimen of 25 to 50 mg diphenhydramine and 500 to 650 mg 
acetaminophen/paracetamol (IV or oral equivalent) is recommended prior to each dose of trial 
drug. This regimen may be modified based on local treatment standards and guidelines as 
appropriate. 
 
PREMEDICATION FOR AVELUMAB ADMINISTRATION AND AVELUMAB SHOULD 
BE ADMINISTERED AFTER TG4001. 
 
 
 
• In the phase II part 2, combination arm and monotreatment arm 
 
Avelumab will be administered at the flat dose 800 mg as an IV infusion over 1 hour [-10 
minutes / +20 minutes, i.e., 50 to 80 minutes].  
Patients will be treated with avelumab once every 2 weeks starting on Day 8, until disease 
progression, unacceptable toxicity, patient withdrawal from the study for any reason, or for a 
maximum of 2 years, whichever occurs first. 
Beyond 2 years of treatment and based on the clinical judgement of the investigator the patient 
could continue to receive study treatments according to the Study Flow-Chart (APPENDIX 
IIID).  
In order to mitigate infusion-related reactions, a premedication regimen of 25 to 50 mg 
diphenhydramine and 500 to 650 mg acetaminophen/paracetamol (IV or oral equivalent) is 
recommended prior to the first 4 infusions of avelumab. This regimen may be modified based 
on local treatment standards and guidelines as appropriate. Premedication should be 
administered for subsequent avelumab doses based upon clinical judgement and 
presence/severity of prior infusion reactions. 
 
FOR 
THE 
COMBINATION 
ARM 
PREMEDICATION 
FOR 
AVELUMAB 
ADMINISTRATION AND AVELUMAB SHOULD BE ADMINISTERED AFTER TG4001. 
 
 Planned study treatment duration and observation period 
 
The trial duration for a patient is estimated to be up to 2.5 years. This includes a 21-day 
screening period (decision will be made in this period for patient’s trial inclusion if all eligibility 

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criteria are met); a treatment duration which may last up to 2 years or beyond based on the  
investigator’s clinical judgement, unless disease progression, unacceptable toxicity, withdrawal 
from the trial or IMP occurs for any reason, an end-of-treatment visit as soon as both IMPs are 
permanently discontinued; and a safety follow-up visit which must occur 30 days after the last 
study treatment administration (See Section 7). At 90 days after the last study treatment 
administration, patients will be contacted by telephone to collect information on new or ongoing 
SAEs and treatment-related non-serious AEs.  Subjects will also be asked about any further 
antineoplastic therapy. 
 
 Planned duration of study treatment in case of related toxicity to one of the IMPs 
 
For the phase Ib, phase II part 1, and phase II part 2 combination arm, the duration of treatment 
lasts from the first study drug administration (TG4001) until the last IMP dose administration 
(TG4001 and/or avelumab).  
- 
In case avelumab has to be stopped for toxicity, TG4001 will be also stopped and the end 
of the study treatment will correspond to the last IMP dose administration. 
- 
In case TG4001 has to be stopped for toxicity, avelumab may be continued alone at the 
discretion of the investigator if a clinical benefit is observed. In this case, the end of study 
treatment will correspond to the date when avelumab is permanently discontinued.  
For the monotreatment arm in phase II part 2, the duration of treatment lasts from the first 
avelumab administration until the last avelumab administration.  
- 
In case avelumab has to be stopped for toxicity, the end of the study treatment will 
correspond to the last avelumab administration 
 
After the patient has been discontinued from IMP(s), he/she will be followed-up until disease 
progression, or death due to any cause or the date of data cut-off, whichever occurs first. 
 
 Planned duration of study treatment according to response 
 
During the study, depending on the response, the following rules for study treatment duration 
will apply: 
• Patients who achieved a confirmed CR MAY stop the treatment earlier at the discretion of 
the investigator provided that they have been treated for a minimum of 12 months. After 
discontinuation of the study treatment, patients will be followed until disease progression 
or death due to any cause or the date of data cut-off, whichever occurs first. 
• Patients with a response of PR/SD will continue to receive TG4001 and avelumab until 
achievement of a confirmed CR, disease progression, development of unacceptable toxicity 
or until they have received a maximum of 2 years of study treatment, whichever occurs first. 
Beyond 2 years of treatment and based on the clinical judgement of the investigator the 
patient could continue to receive study treatments according to the Study Flow-Chart 
(APPENDIX IIIB and D).  
• Patients with progressive disease (PD) based on RECIST 1.1 will stop treatment and 
complete the off-treatment procedures in phase I and phase II part 1. In phase II part 2 at 
the 1st radiologic evidence of PD, clinically stable patients may continue study treatment at 
the Investigator’s discretion while awaiting confirmatory scan. If repeat imaging confirms 
PD, study treatment must be discontinued except if the patient is clinically stable or 
clinically improved, and there is no further increase in the target lesions, no unequivocal 
increase in non-target disease, and no additional new lesions (non-worsening PD). If repeat 

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scan shows SD, PR or CR patient continues study treatment and imaging assessment should 
be performed every 6 weeks.  
• Patients who are withdrawn from study drug treatment for reasons other than disease 
progression based on RECIST 1.1 will be followed until disease progression or death due 
to any cause or the date of data cut-off, whichever occurs first. 
 
For any patient, as soon study treatment is permanently discontinued, an “end of treatment visit” 
will be completed in the eCRF (See Section 7.4). 
 
 Concomitant therapies and medications 
 
 Concomitant medications 
 
Concomitant medications are: 
- 
Medications and/or non-drug therapies taken by the patient during the month before Day 1 
of study treatment (i.e., start of the study treatment), and continuing after the start of the 
study treatment 
- 
All medications and non-drug therapies taken during the treatment period of the study 
starting from start of study treatment up to 30 days after the last study treatment 
administration 
 
Concomitant medications will be reported in the eCRF with their reason for prescription, start 
date and end date, route of administration and dose. 
Any prior medication or significant non-drug therapies ending within 1 month prior to the start 
of the study treatment will be reported in the eCRF in the same way. 
 
 Permitted medicines and therapies 
 
• Any medications (other than those excluded by the study protocol) that are considered 
necessary for the patient’s 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: 
erythropoietin, antiemetics, amifostine, folates, vitamin B12 and vitamin D. 
• The use of systemic corticosteroids during the study is restricted as follows: for short term 
treatment (≤ 7 days) of allergic reactions or for the treatment of irAEs, or for replacement 
for adrenal insufficiency at doses equivalent to ≤ 10 mg prednisone daily (see Section 
6.3.4). 
• Radiotherapy for pain relief (e.g., bone metastases) is permitted. If lesions are in the field 
of radiation they will no longer be evaluable for the tumor response, patients receiving 
palliative radiotherapy will be analyzed separately.  
 
 Non-permitted medicines and therapies 
 
• Any live vaccine for the prevention of infectious disease (e.g., human papilloma virus 
vaccine). 
• Growth factors (granulocyte colony stimulating factor or granulocyte macrophage colony 
stimulating factor), except erythropoietin and darbepoietin alpha (may be prescribed at the 
investigator’s discretion). 

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• Bisphosphonate or denosumab treatment is not allowed unless it has been initiated more 
than 14 days prior to receiving the first administration of study treatment.  
If the administration of a non-permitted concomitant drug becomes necessary during the trial, 
the patient will be withdrawn from study treatment (the Sponsor may be contacted to discuss 
whether the study treatment must be discontinued). 
 
 
 Considerations for Steroids use during the trial 
 
Data indicate that corticosteroids have an adverse effect on T cell function (Schleimer R.P. et 
al., 1984) and that they inhibit and damage lymphocytes (Khan M.M., 2008). Furthermore, as 
with all immunotherapies intended to augment cell-mediated immunity, there is a risk that 
concomitant immunosuppressives such as steroids will counteract the intended benefit. 
However, studies with anti-CTL-A4 compounds indicate that short term use of steroids can be 
employed without compromising clinical outcomes (Weber J.S. et al., 2012). Therefore, the use 
of steroids during this trial is restricted as follows: 
• Therapeutic use: limited to the treatment of infusion-related reactions and for short term 
treatment (≤ 7 days) of allergic reactions or for the treatment of irAEs. The course of steroid 
treatment should be completed as soon as clinically feasible and before resuming the next 
cycle provided the event has resolved to a Grade 1 or less. 
• Physiologic use: replacement for adrenal insufficiency at doses equivalent to ≤ 10 mg 
prednisone daily are acceptable. 
Prophylactic use: prophylactic use, e.g. for the prevention of acute infusion-related reactions, 
constitutes concomitant use and is prohibited. 
 
 Other trial considerations 
 
The following non-drug therapies must not be administered during the study (and within 28 
days before the start of trial treatment): 
• Major surgery (excluding biopsy). 
• Herbal remedies with immunostimulating properties (e.g., mistle toe extract) or known to 
potentially interfere with major organ function (e.g., hypericin). 
Patients should not abuse alcohol or other drugs during the study. 
 
 Special precautions 
 
 
Patients must be observed for 1 hour post-administration of avelumab for the first four 
infusions, in an area with resuscitation equipment and emergency agents. Immediate emergency 
treatment of an infusion-related reaction or a severe hypersensitivity reaction must be assured 
according to institutional standards. In order to treat possible anaphylactic reactions appropriate 
medical therapy (including epinephrine, corticosteroids, IV antihistamines, bronchodilators, 
and oxygen) must be available along with equipment for assisted ventilation. For subsequent 
infusions and if no infusion-related reactions have been observed during/after the first 4 
administrations, observation time can be reduced to at least 30 minutes after completion of each 
infusion. 

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Investigators should also monitor patients closely for potential irAEs, which may become 
manifest at the earliest after weeks of treatment. Such events may consist of persistent rash, 
diarrhea and colitis, autoimmune hepatitis, arthritis, glomerulonephritis, cardiomyopathy, or 
uveitis and other inflammatory eye conditions. The spectrum of hypothetical irAEs also 
includes formation of auto-antibodies like ANAs or ANCAs (see Section 6.5.2.6 for details on 
the management of irAEs). 
 Method of assigning patients to treatment groups 
 
 Recruitment 
 
Upon signing the informed consent form (ICF), the patient will be assigned an identification 
number which is a combination of the center number and the patient number. 
The center number is assigned by the Sponsor to the investigational site. At each site, the first 
patient screened is assigned patient number 01, and subsequent patients are assigned 
consecutive numbers. Once assigned to a patient, the patient number will not be reused. 
The screening process will start and is defined as the baseline period. The baseline lasts at most 
21 days. 
 
If the patient fails to be included for any reason, the reason for non-inclusion (e.g. withdrawal 
of consent, exclusion criteria) and a minimum of other parameters will be entered in the eCRF. 
Under no circumstances will a patient screened and found not eligible for the study be permitted 
to be re-screened for a second time. 
 
 Randomization  
 
Non applicable for the phase Ib and the phase II part 1.  
Randomization is applicable for the phase II part 2. 
Upon satisfying all inclusion and exclusion criteria, the Investigator or his/her delegate will 
proceed to randomization which will be done in the eCRF. 
 
• In patients without liver metastases at baseline randomization will be conducted equally 
in a 1:1 ratio TG4001 with avelumab (combination arm) versus avelumab alone 
(monotreatment arm). A stratification will be done on primary tumor site. 
• In patients with liver metastases at baseline randomization will be conducted equally in 
a 1:1 ratio TG4001 with avelumab versus avelumab alone, no stratification will be 
performed. 
 
The patient must start the study treatment according to allocation during randomization on the 
day of randomization (+1 day) if randomized into the combination arm and 1 week after 
randomization (+/- 1 day) if randomized into the monotreatment arm. 
 
 Dose modifications  
 
There will be no delay or dose reduction for TG4001 and avelumab in this study.  
If an AE is related to only one agent (TG4001 or avelumab) and dose cancellation is required, 
the other agent continues as planned, if applicable. 

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In case of occurrence of symptoms compatible with SARS-CoV-2 (COVID-19) infection or in 
case of SARS-CoV-2 (COVID-19) positive testing, administration of TG4001 and avelumab 
will be performed based on the clinical judgement by the investigator.   
 
 TG4001  
 
6.5.1.1.TG4001 dose modification 
 
For a given patient, no dose modification of TG4001 is permitted.  
Criteria for administration of TG4001 are defined as follows: 
- neutrophils ≥ 0.5 x 109/L 
- if a Grade 1-2 AE occurs, TG4001 should be administered as planned. 
- in case ≥ Grade 3 AE possibly, probably or definitely suspected to be related to TG4001 
occurs, the administration of TG4001 will be cancelled and the patient should come in for 
his/her next, regularly scheduled visit. The next scheduled visit should occur according to the 
patient’s next regularly scheduled visit relative to Day 1. 
 
In case the patient misses 2 consecutives doses of TG4001, contact the sponsor for guidance. 
 
TG4001 does not have to be omitted for avelumab related AEs, if applicable. Contact the 
sponsor for guidance. 
 
For phase Ib, phase II part 1 and phase II part 2 combination arm: In case TG4001 must be 
discontinued due to toxicity or other reason than disease progression, the other IMP (avelumab) 
may be continued as planned at the discretion of the investigator if a clinical benefit is observed. 
 
 Avelumab 
 
6.5.2.1.Avelumab dose modification 
 
No dose delay or dose reduction of avelumab will be allowed in this study. 
A time window of +/- 1 day up to Day 36 and of -3/+1 days beyond Day 36 will be permitted 
for all trials procedures. However, the bi-weekly schedule should be strictly adhered to, and 
patients should return to the target date (i.e. the next regularly scheduled visit relative to the 
start of avelumab) even if the previous visit was off schedule.  
 
In case the patient misses 2 consecutives doses of avelumab, contact the sponsor for guidance. 
 
Avelumab does not have to be omitted for TG4001 related AEs, if applicable. Contact the 
sponsor for guidance. 
 
For phase Ib, phase II part 1 and phase II part 2 combination arm: In case avelumab must be 
discontinued due to toxicity or other reason than disease progression, TG4001 will be stopped 
as well and the patient will be followed-up until disease progression, death, or study cut off 
date, whichever occurs first. 
For phase II part 2 monotreatment arm: In case avelumab must be discontinued due to toxicity 
or other reason than disease progression, the patient will be followed-up until disease 
progression, death, or study cut off date, whichever occurs first. 
 

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6.5.2.2.Adverse drug reactions requiring avelumab treatment modification or discontinuation  
 
Dosing withhold or discontinuation may be required based on individual safety and tolerability 
(Table 6-2 below, Summary of Product Characteristics, 19 October 2022, or later version, 
if available). Resume avelumab in patients whose adverse reactions recover to Grade 1 or 
resolved. 
Table 6-2:  Treatment Modification Recommendations for Treatment-related Adverse 
Reactions  
Treatment-related Adverse 
Reaction 
Severity 
Treatment modification 
Pneumonitis 
Grade 2 pneumonitis 
Withhold avelumab. 
Resume avelumab in 
patients with complete or 
partial resolution (Grade 0 
to 1) of pneumonitis after 
corticosteroid taper. 
Grade 3 or Grade 4 pneumonitis or recurrent Grade 2 
pneumonitis 
Permanently discontinue 
Hepatitis 
AST or ALT more than 3 and up to 5 times ULN or 
total bilirubin more than 1.5 and up to 3 times ULN 
Withhold avelumab. 
Resume avelumab in 
patients with complete or 
partial resolution (Grade 0 
to 1) of hepatitis after 
corticosteroid taper. 
AST or ALT more than 5 times ULN or total bilirubin 
more than 3 times ULN 
Permanently discontinue 
Colitis 
Grade 2 or Grade 3 diarrhoea or colitis 
Withhold avelumab. 
Resume avelumab in 
patients with complete or 
partial resolution (Grade 0 
to 1) of colitis or diarrhoea 
after corticosteroid taper. 
Grade 4 diarrhoea or colitis or recurrent Grade 3 
diarrhoea or colitis 
Permanently discontinue 
Endocrinopathies (including but 
not limited to hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, hyperglycaemia) 
Grade 3 or Grade 4 
Withhold avelumab. 
Resume avelumab in 
patients with complete or 
partial resolution (Grade 0 
to 1) of endocrinopathies 
after corticosteroid taper. 
Nephritis and Renal dysfunction Serum creatinine more than 1.5 and up to 6 times ULN Withhold avelumab. 
Resume avelumab in 
patients with complete or 
partial resolution (Grade 0 
to 1) of nephritis and renal 
dysfunction after 
corticosteroid taper. 
Serum creatinine more than 6 times ULN 
Permanently discontinue 
Skin reactions 
Grade 3 rash 
Withhold until adverse 
reactions recover to 
Grade 0-1 
Grade 4 or recurrent Grade 3 rash or confirmed 
Stevens–Johnson syndrome (SJS) or Toxic epidermal 
necrolysis (TEN) 
Permanently discontinue 

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Treatment-related Adverse 
Reaction 
Severity 
Treatment modification 
Other immune-related adverse 
reactions (including myositis, 
hypopituitarism, uveitis, 
myasthenia gravis, myasthenic 
syndrome, Guillain-Barré 
syndrome) 
For any of the following: 
• 
Grade 2 or Grade 3 clinical signs or symptoms of 
an immune-related adverse reaction not described 
above. 
• 
Grade 3 or 4 endocrinopathies 
Withhold avelumab. 
Resume avelumab in 
patients with complete or 
partial resolution (Grade 0 
to 1) of other 
immune-related adverse 
events after corticosteroid 
taper. 
For any of the following: 
• 
Life threatening or Grade 4 adverse reactions 
(excluding endocrinopathies controlled with 
hormone replacement therapy)  
• 
Recurrent Grade 3 immune-related adverse 
reaction 
• 
Requirement for 10 mg per day or greater 
prednisone or equivalent for more than 12 weeks 
• 
Persistent Grade 2 or 3 immune-related adverse 
reactions lasting 12 weeks or longer 
Permanently discontinue 
Infusion-related reactions 
Grade 1 infusion-related reaction 
Reduce infusion rate by 
50% 
Grade 2 infusion-related reaction 
Withhold until adverse 
reactions recover to 
Grade 0-1; restart infusion 
with a 50% slower rate 
Grade 3 or Grade 4 infusion-related reaction 
Permanently discontinue 
Pancreatitis 
Suspected pancreatitis 
Withhold 
Confirmed pancreatitis 
Permanently discontinue 
Myocarditis 
Suspected myocarditis 
Withhold 
Confirmed myocarditis 
Permanently discontinue 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal. 
Note: toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse 
Events Version 4.0 (NCI-CTCAE v4.0). 
 
Infusion-related reactions, hypersensitivity reactions and irAEs should be handled according to 
guidelines as detailed in Sections 6.5.2.3, 6.5.2.4 and 6.5.2.6. 
  
6.5.2.3.Management of infusion-related reactions  
 
Patients are at risk of developing infusion-related reactions including drug hypersensitivity 
reactions, mainly mild to moderate, but which may also be life-threatening.  
 
Immediate access to an intensive care unit or equivalent environment and appropriate medical 
therapy (including epinephrine, corticosteroids, IV antihistamines, bronchodilators, and 
oxygen) must be available for use in the treatment of infusion-related reactions. Infusion of 
avelumab will be stopped in case of Grade ≥ 2 infusion-related, allergic, or anaphylactoid 
reactions.  Patients must be observed for 1 hour post-administration of avelumab for the first 
four infusions. For subsequent infusions and if no infusion-related reactions have been observed 
during/after the first 4 administrations, observation time can be reduced to at least 30 minutes 
after completion of each infusion. 
 
For phase Ib and phase II part 1: In order to mitigate infusion-related reaction, premedication 
with a histamine H1 receptor blocker and with paracetamol (acetaminophen) is mandatory prior 
to each dose of avelumab 

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For phase II part 2: In order to mitigate IRRs, patients have to be premedicated with an 
antihistamine and with paracetamol (acetaminophen) prior to the first 4 infusions of avelumab. 
Monitor patients for signs and symptoms of IRRs including pyrexia, chills, flushing, 
hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the 
rate of infusion for mild or moderate IRRs. Stop the infusion and permanently discontinue 
avelumab for severe (Grade 3) or life-threatening (Grade 4) IRRs. Premedication should be 
administered for subsequent avelumab doses based upon clinical judgement and 
presence/severity of prior infusion reactions (See Section 6.1.2). 
  
In case of occurrence of infusion-related reaction, please follow the guidelines for the treatment 
modifications of avelumab described in Table 6-3 below, Avelumab Investigator’s Brochure 
Version 8, 16 May 2018, Section 6.1.2 or later version if available. 
 
Table 6-3:  Treatment Modification for Symptoms of Infusion-Related Reactions Caused 
by Avelumab 
NCI-CTCAE Grade  
Treatment Modification for Avelumab 
Grade 1 – mild 
• Mild transient reaction; infusion interruption not 
indicated; intervention not indicated 
 
• Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening 
Grade 2 – moderate 
• Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for  24h 
 
• Temporarily discontinue avelumab infusion 
• Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity, and monitor closely 
for any worsening  
Grade 3 or Grade 4 – severe or life-threatening 
• Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms 
following initial improvement; hospitalization 
indicated for clinical sequelae 
• Grade 4: Life-threatening consequences; urgent 
intervention indicated 
 
• Stop the avelumab infusion immediately and 
disconnect infusion tubing from the subject 
• Subjects have to be withdrawn immediately from 
avelumab treatment and must not receive any 
further avelumab treatment 
IV: intravenous; NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Event; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
 
6.5.2.4.Management of severe hypersensitivity reaction and flu-like syndrome  
 
Immediate access to an intensive care unit or equivalent environment and appropriate medical 
therapy (including epinephrine, corticosteroids, IV antihistamines, bronchodilators, and 
oxygen) must be available for use in the treatment of infusion-related reactions. Infusion of 
avelumab will be stopped in case of Grade ≥ 2 infusion-related, allergic, or anaphylactoid 
reactions.  Patients must be observed for 1 hour post-administration of avelumab for the first 
four infusions. For subsequent infusions and if no infusion-related reactions have been observed 
during/after the first 4 administrations, observation time can be reduced to at least 30 minutes 
after completion of each infusion. 
Patients should be instructed to report any delayed reactions to the investigator immediately. 
 
Symptoms of hypersensitivity reactions include 
• 
Impaired airway 
• 
Decreased oxygen saturation (<92%) 

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• 
Confusion 
• 
Lethargy 
• 
Hypotension 
• 
Pale/clammy skin 
• 
Cyanosis 
 
For prophylaxis of flu-like symptoms, 25 mg indomethacin or comparable NSAID dose (e.g., 
ibuprofen 600 mg, naproxen sodium 500 mg) may be administered 2 hours before and 8 hours 
after the start of each dose of avelumab i.v. infusion. Alternative treatments for fever (e.g., 
paracetamol) may be given to patients at the discretion of the investigator. 
 
6.5.2.5.Management of tumor lysis  
 
In addition, since avelumab can induce ADCC, there is a potential risk of tumor lysis syndrome. 
Should this occur, patients should be treated as per local guidelines and the management 
algorithm published by Howard et al (Howard S.C. et al., 2011). 
 
6.5.2.6.Management of immune related adverse events  
 
Immune-mediated adverse reactions (immune-related pneumonitis, immune-related colitis, 
immune-related hepatitis, immune-related pancreatitis, immune-related myocarditis, immune-
related endocrinopathies (thyroid disorders, adrenal insufficiency, new onset type I diabetes 
mellitus, pituitary disorders), immune-related nephritis and renal dysfunction and other 
immune-related AEs (myositis, Guillain-Barré syndrome, uveitis and myasthenia gravis / 
myasthenic syndrome) have been identified as important risks for avelumab. Such events 
should be recognized early and treated promptly to avoid potential major complications. 
For suspected immune-related adverse reactions, adequate evaluation should be performed to 
confirm aetiology or exclude other causes. The administration of avelumab may be cancelled 
due to severe or unresolved toxicity or undercurrent AEs. 
 
Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE grade): 
• Grade 1 to 2: treat symptomatically or with moderate dose steroids, more frequent 
monitoring 
• Grade 1 to 2 (persistent):  manage similar to high grade AE (Grade 3 to 4) 
• Grade 3 to 4:  treat with high dose corticosteroids 
Treatment of irAEs should follow guidelines set forth in Table 6-4 below, Avelumab 
Investigator’s Brochure Version 8, 16 May 2018 Section 9.2 or later version if available. 
 
 
 
Table 6-4: Management of Immune-related Adverse Events 
 

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Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhoea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (e.g. 
loperamide) 
Close monitoring for worsening symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2, 3 or 4.  
Grade 2  
Diarrhoea: 4 to 6 stools per day over 
Baseline; IV fluids indicated < 24 
hours; not interfering with ADL 
Colitis: abdominal pain; blood in 
stool  
 
Withhold avelumab therapy 
Symptomatic treatment 
If improves to Grade ≤ 1:  
Resume avelumab therapy 
 
If persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhoea (Grade 3): ≥ 7 stools per 
day over Baseline; incontinence; IV 
fluids ≥ 24 h; interfering with ADL 
Colitis (Grade 3):  severe abdominal 
pain, medical intervention indicated, 
peritoneal signs 
Grade 4: life-threatening, perforation 
Withhold avelumab for 
Grade 3. 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
 
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider lower endoscopy  
If improves:  
Continue steroids until Grade ≤ 1, then taper 
over at least 1 month; resume avelumab 
therapy following steroids taper (for initial 
Grade 3).  
 
If worsens, persists > 3 to 5 days, or recurs 
after improvement: 
Add infliximab 5mg/kg (if no contraindication). 
Note: infliximab should not be used in cases 
of perforation or sepsis.  
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface area  
Continue avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
If Grade 2 persists > 1 to 2 weeks or recurs:  
Withhold avelumab therapy  
Consider skin biopsy  
 
Consider 0.5-1.0 mg/kg/day prednisone or 
equivalent. Once improving, taper steroids 
over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and 
resume avelumab therapy following steroids 
taper. 
If worsens:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area;  
Grade 4: Life threatening 
consequences  
Withhold avelumab for 
Grade 3. 
Permanently discontinue for 
Grade 4 or recurrent Grade 3.  
Consider skin biopsy  
Dermatology consult  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month; resume 
avelumab therapy following steroids taper (for 
initial Grade 3) 

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1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only  
Consider withholding 
avelumab therapy  
Monitor for symptoms every 
2 to 3 days  
Consider Pulmonary and 
Infectious Disease consults  
Re-assess at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4.  
Grade 2 
Mild to moderate new symptoms  
Withhold avelumab therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade ≤ 1, taper 
steroids over at least 1 month, and then 
resume avelumab therapy following steroids 
taper  
If not improving after 2 weeks or worsening or 
for recurrent Grade 2:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4:  Life-threatening  
Permanently discontinue 
avelumab therapy. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month  
If not improving after 48 hours or worsening:  
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, IV 
immunoglobulin, or mycophenolate mofetil)  
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Grade 1 AST or ALT > ULN to 3.0 x 
ULN and/or Total bilirubin > ULN to 
1.5 x ULN  
Continue avelumab therapy 
Continue liver function monitoring  
If worsens:  
 Treat as Grade 2 or 3 to 4.  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 x 
ULN  
Withhold avelumab therapy 
Increase frequency of 
monitoring to every 3 days. 
 
If returns to Grade ≤ 1: 
Resume routine monitoring; resume 
avelumab therapy. 
If elevation persists > 5 to 7 days or worsens:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
Permanently discontinue 
avelumab therapy  
If returns to Grade ≤ 1:  

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AST or ALT > 5 x ULN and/or total 
bilirubin > 3 x ULN  
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consult gastroenterologist/ 
hepatologist 
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted  
Taper steroids over at least 1 month  
If does not improve in > 3 to 5 days, worsens 
or rebounds:  
Add mycophenolate mofetil 1 gram (g) twice 
daily  
If no response within an additional 3 to 5 
days, consider other immunosuppressants 
per local guidelines. 
Renal irAEs 
Grade of Creatinine Increased 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 1.5 x 
ULN 
Continue avelumab therapy 
Continue renal function monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 6 x 
ULN 
 
 
 
 
 
Withhold avelumab therapy 
Increase frequency of monitoring to 
every 3 days 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to Grade ≤1: 
Taper steroids over at least 1 month, 
and resume avelumab therapy 
following steroids taper. 
If worsens:  
Treat as Grade 4. 
Grade 4 
Creatinine increased > 6 x ULN 
 
 
 
 
 
 
 
Permanently discontinue avelumab 
therapy 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
If returns to Grade ≤1: 
Taper steroids over at least 1 month. 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-muscle/brain, BNP) or 
cardiac imaging abnormalities 
suggestive of myocarditis.  
Withhold avelumab therapy. 
Hospitalize. 
In the presence of life threatening cardiac 
decompensation, consider transfer to a 
facility experienced in advanced heart 
failure and arrhythmia management. 
Cardiology consult to establish etiology 
and rule-out immune-related myocarditis.  
Guideline based supportive treatment as 
per cardiology consult.* 
 
Consider myocardial biopsy if 
recommended per cardiology consult. 
If 
symptoms 
improve 
and 
immune-related etiology is ruled 
out, re-start avelumab therapy. 
 
If symptoms do not 
improve/worsen, viral myocarditis 
is excluded, and immune-related 
etiology is suspected or confirmed 
following cardiology consult, 
manage as immune-related 
myocarditis. 

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Immune-related myocarditis 
Permanently discontinue avelumab. 
Guideline based supportive treatment as 
appropriate as per cardiology consult.* 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids over 
at least 1 month. 
 
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A). 
*Local guidelines, or eg. European Society of Cardiology or American Heart Association guidelines  
European Society of Cardiology guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
American Heart Association guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, Type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if needed 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, Type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Resume avelumab once symptoms 
and/or laboratory tests improve to 
Grade ≤ 1 (with or without hormone 
replacement/suppression). 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate.  
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum thyroxine with 
inappropriately low thyroid-stimulating 
hormone and/or low serum cortisol 
with inappropriately low 
adrenocorticotropic hormone): 
• 
Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in 
women)  
• 
Hormone 
replacement/suppressive therapy 
as appropriate  
Resume avelumab once symptoms 
and hormone tests improve to 
Grade ≤ 1 (with or without hormone 
replacement). 
 
In addition, for hypophysitis with 
abnormal MRI, resume avelumab 
only once shrinkage of the pituitary 
gland on MRI/CT scan is 
documented.  
 
Continue hormone 
replacement/suppression therapy 
as appropriate. 

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• 
Perform pituitary MRI and visual 
field examination as indicated 
 
If hypophysitis confirmed: 
• 
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month 
• 
Withhold avelumab if moderate, 
severe or life-threatening 
symptoms of hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) followed 
by corticosteroids taper during at 
least 1 month. 
• 
Add prophylactic antibiotics for 
opportunistic infections. 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE 
Withhold avelumab therapy pending 
clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-starting 
avelumab therapy 
If irAE is confirmed, treat as Grade 
2 or 3 irAE. 
Grade 2 irAE or first occurrence 
of Grade 3 irAE 
Withhold avelumab therapy 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent   
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
and resume avelumab therapy 
following steroids taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month. 
Grade 4  
 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent and/or other 
immunosuppressant as needed 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult. 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Permanently discontinue avelumab 
therapy 
Specialty consult 
 

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Abbreviations: ADL = activities of daily living; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BNP = B-type natriuretic peptide; CK = creatine kinase; CT = computed tomography; FSH = follicle-stimulating 
hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; irAE = immune-related adverse event; IV = 
intravenous; LH = luteinizing hormone; MRI = magnetic resonance imaging; NCI-CTCAE = National Cancer 
Institute-Common Terminology Criteria for Adverse Events; PRL = prolactin; ULN = upper limit of normal. 
 
In addition, please refer to American Society of Clinical Oncology guideline for management 
of irAEs (November 2021). 
 
6.5.2.7. Treatment of overdose 
 
For an administration at a dose of 10 mg/kg an overdose is defined as any dose ≥ 10% than the 
calculated dose for that particular administration (phase Ib and phase II part 1). Any overdose 
must be recorded in the trial medication section of the eCRF. 
For an administration at a flat dose of 800 mg an overdose is defined as any dose above 800 mg 
(phase II part 2). Any overdose must be recorded in the trial medication section of the eCRF. 
There are no known symptoms of avelumab overdose to date. Treatment must be directed to 
symptoms. 
 
 Blinding / Unblinding 
 
Not applicable. 
 
 Treatment compliance 
 
 Dispensing and accountability 
 
The IMPs will only be dispensed, according to Investigator’s prescription, to patients who meet 
all selection criteria. 
 
The Investigator / Pharmacist or delegated person will maintain IMP accountability records for 
TG4001 as well as for avelumab, 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 visits. All used and 
unused IMPs will be accounted for. All unused IMP will be destroyed locally or returned to 
Transgene and/or its IMP supply provider, providing destruction or return certificates.  
 
 Assessment of compliance 
 
The compliance for the IMPs will be monitored through the IMP(s) accountability logs and 
information reported on the eCRF pages. 
 
 End of treatment visit 
 
An end of treatment visit will be performed as soon as study treatment(s) is/are stopped for 
whatever reason (e.g. disease progression, unacceptable toxicity, premature discontinuation due 
to any reason).  
 

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For any patient, as soon as one of the above situations occurs, an “end of treatment visit” will 
be completed in the eCRF. The Investigator will obtain all the required details and document 
the date and the reason for study treatment discontinuation in the eCRF “end of treatment” 
form.  
 
The patient will then be followed for PFS (if applicable), safety (safety visit), subsequent 
therapies and survival. 
 
 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.  
 
 Follow-up for PFS and subsequent antineoplastic therapy 
 
In case the study treatment discontinuation is not due to progressive disease or death, the patient 
will be followed for PFS until progressive disease by RECIST 1.1 or until the date of last contact 
if the patient is lost to follow-up or withdraws consent. A CT scan or MRI of measurable and 
non-measurable disease must be obtained every 6 weeks until disease progression or for a 
period of 9 months after the start of study treatment. Beyond 9 months, the evaluations will be 
performed every 12 weeks until disease progression (see Section 7). 
Tumor assessments will be 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 
 
All patients (if alive) who discontinue the study treatment, will be evaluated for safety 30 days 
after the last study treatment administration, including those who refuse to return for a visit who 
will be contacted by phone. A “safety follow-up visit” will then be completed in the eCRF. 
Concomitant medications and significant non-drug therapies prescribed within 30 days after the 
last study treatment administration will be collected. 
At 90 days after the last study treatment administration, patients will be contacted by telephone 
to collect information on new or ongoing SAEs and treatment-related non-serious AEs.  
Subjects will also be asked about any further antineoplastic therapy. Corresponding pages will 
have to be completed in the eCRF. 
 
 Follow-up for survival and subsequent antineoplastic therapy 
 
From the safety follow-up visit or last PFS follow-up visit, the patient will be followed every 3 
months for survival until death or the date of last contact if the patient is lost to follow-up or 
withdraws consent. All subsequent antineoplastic therapies (if applicable) must be recorded in 
the eCRF with start and end dates. 
 
7 STUDY VISITS AND PROCEDURES 
 

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A flow-chart shown in Appendix III summarizes the evaluations to be performed along with 
the time points and the data to be collected in the eCRF. If not otherwise specified, when an 
assessment is planned on the same day as study treatment administration, it will be done prior 
to it. 
 
 Evaluations description 
 
The following parameters will be measured during the course of the study: 
 
Inclusion/exclusion criteria 
Patient eligibility is to be established by the investigator by confirming all inclusion/exclusion 
criteria are met. Violation of any entry criterion excludes a patient from enrolment into the 
study. 
 
Demography 
- 
Date of birth, gender 
- 
Child bearing potential status  
- 
Smoking habits  
- 
Alcohol consumption 
 
History of studied disease 
- 
Date of diagnosis and stage at diagnosis 
- 
Histology type 
- 
HPV status 
- 
Prior antineoplastic therapy  
 
Relevant medical history and current medical conditions 
- 
Relevant medical history with established diagnosis (e.g., cholecystectomy, ongoing arterial 
hypertension) present or recovered at ICF signature  
- 
Syndrome / pathology with established diagnosis (e.g., gastro-oesophageal reflux) starting 
during the screening period (from signature of ICF up to start of study treatment) either 
recovered or ongoing 
 
Signs and symptoms pre-treatment 
- 
Relevant signs and symptoms (e.g., cough, dyspnea, pain) present at the signature of the 
ICF or starting during the screening period 
 
Clinical evaluation 
- 
Physical examination of the major organ system, including vital signs (body temperature, 
pulse and blood pressure), oxygen saturation by pulse oximetry on room air (only for phase 
II part 2) and weight  
- 
Height will be collected only at baseline. 
- 
PS on ECOG scale (Appendix I) 
 
Cardiac evaluation 
- 
Electrocardiogram (12 leads)  
- 
In case of potential symptoms of myocarditis / pericarditis during study treatment (such as 
chest pain, shortness of breath, heart palpitations, and reduced tolerance to exercise), cardiac 
laboratory analyses (e.g. creatinine kinase-mycardial band, troponin), ECG and 

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echocardiography (or MUGA scan) will be requested. If abnormal findings indicate 
possible myo- or pericarditis, the patient will be referred to consulting a cardiologist. 
 
Safety assessment 
- 
All SAEs from ICF signature  
- 
New AEs including worsening of pre-existing medical condition or signs/symptoms (e.g. 
worsening of arterial hypertension, worsening of pain) from start of study treatment  
- 
Follow-up of all ongoing AEs 
 
Collection of concomitant medications and significant non-drug therapies 
 
Laboratory evaluation (blood analyses) 
- 
Hematology: complete blood count including Red Blood Cells, hemoglobin, hematocrit, 
WBC and differential, platelets 
- 
Biochemistry analysis including: ALT, AST, LDH, alkaline phosphatases, total bilirubin, 
lipase, amylase, serum protein and serum albumin, electrolytes (Na+, K+, Cl-, Ca++), 
glucose 
- 
Renal tests: creatinine (and calculated creatinine clearance at baseline) 
- 
Free T4, TSH 
- 
HIV and HCV serology, detection of antigen HBs at baseline  
- 
Pregnancy test (for women of childbearing potential) 
 
Immunology and translational research on blood and tumor biopsy samples 
- 
 
 
  
 
 
 
 
 
  
 
Tumor evaluation: 
- 
All measurable and non-measurable lesions as identified at baseline must be assessed using 
the same methods and techniques over the whole study period. Tumor evaluation will be 
assessed based on RECIST version 1.1. Additional CT or MRI may be performed in case 
of suspected new site of metastases. 
- 
The tumor assessment must be performed every 6 weeks for the first 9 months from 
treatment start and every 12 weeks thereafter, with a time window allowed of +/-7 days 
(except for baseline). As far as possible, tumor assessment should be performed prior to the 
visit. The first CT scan or MRI post-baseline must be performed after at least 5 weeks of 
treatment. 
 
Further antineoplastic therapies 
All subsequent anti-neoplastic therapies given after the patient discontinued the study treatment 
period will be collected in the eCRF. 
 
 Baseline 
 
The following evaluations must be performed within 21 days prior to the initiation of treatment: 
- 
Inclusion/exclusion criteria check 

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- 
Physical examination of the major organ system, including vital signs, weight and height 
- 
PS on ECOG scale 
- 
Demography 
- 
History of studied disease (including prior antineoplastic treatments) 
- 
Relevant medical history / current medical conditions and signs and symptoms 
- 
Serious adverse events reporting (from the date of signature of the ICF) 
- 
Concomitant medications and significant non-drug therapies collection and medications 
administered during the month prior to start of study treatment 
- 
Tumor sample on biopsy (mandatory for phase Ib and phase II part 1; mandatory only for 
patients with accessible lesions in phase II part 2) 
- 
HPV status 
- 
HIV and HCV serology, detection of antigen HBs for phase II part 2 
- 
Tumor evaluation 
• by preferably CT (or MRI) of the head and neck, chest, abdomen and all other 
known sites of disease (e.g. pelvis, if applicable) and other established assessments 
of tumor burden if CT / MRI imaging is insufficient for the individual patient. In 
case of bone pain, an adequate radiological and/or isotopical exploration is to be 
performed to research metastases 
 
The following evaluations must be performed within 7 days prior to the initiation of treatment, 
within 3 days prior to randomization for phase II part 2: 
- 
Inclusion/exclusion criteria check 
- 
12-leads Electrocardiogram 
- 
Pulse oximetry on room air only for phase II part 2 
- 
Blood analyses: 
• Hematology, biochemistry, creatinine,  
• Free T4, TSH 
• HIV and HCV serology, detection of antigen HBs only for phase Ib and phase II part1 
• Pregnancy test for women of childbearing potential 
• Blood sample collection for immunomonitoring 
 
 During the study treatment period 
 
The time windows allowed for the visits are: 
- 
+/- 1 day from Day 1 to Day 36 
- 
- 3/+1 days for the further study treatment visits beyond Day 36 
 
Tumor evaluation must be performed every 6 weeks for the first 9 months after treatment start 
and every 12 weeks thereafter, with a time window allowed of +/-7 days. 
 
12-leads ECG during treatment period as clinically indicated. 
In case of potential symptoms of myocarditis / pericarditis during study treatment (such as chest 
pain, shortness of breath, heart palpitations, and reduced tolerance to exercise), cardiac 
laboratory analyses (e.g. creatinine kinase-myocardial band, troponin), ECG and 
echocardiography (or MUGA scan) will be requested. If abnormal findings indicate possible 
myo- or pericarditis, the patient will be referred to consulting a cardiologist. 
 
From Day 1 to Day 36 
- 
Physical examination* including vital signs and body weight on Days 1, 8, 15, 22, 29, 36  

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- 
Performance status* on Days 1, 15, 29 
- 
Adverse events reporting on Days 1, 8, 15, 22, 29, 36 
- 
Concomitant medications and non-drug therapies collection on Days 1, 8, 15, 22, 29, 36 
- 
Hematology* on Days 1 (not for phase II part 2), 8, 15, 22, 29, and 36 
- 
Biochemistry*, creatinine* on Days 1 (not for phase II part 2), 8, 15, 22, 29, and 36 
- 
TSH on Day 36* 
- 
Blood pregnancy test* for women of childbearing potential on Day 36 
- 
Type I and II HLA on Day 1* (not for phase II part 2) 
- 
Blood sample collection for immunomonitoring* on Days 1, 8 and D15 (D15 for phase II 
part 2 only); on Day 1, 6 hours post-dose for patients randomized in the combination arm 
and treated with TG4001 (for phase II part 2 only) 
- 
Inclusion/exclusion criteria check on Day 1 
- 
Randomization on Day 1 for phase II part 2 
- 
TG4001 SC administration once a week on Days 1, 8, 15, 22, 29, and 36 (phase Ib, phase 
II part 1 and phase II part 2 combination arm) 
- 
Avelumab IV administration once every 2 weeks starting on Day 8 (D22 and D36) for all 
patients  
 
Beyond Day 36 up to Month 6, Day 204  
- 
Physical examination* including vital signs, body weight and performance status every 2   
weeks   
- 
Adverse events reporting every 2 weeks 
- 
Concomitant medications and non-drug therapies collection every 2 weeks 
- 
Hematology* every 2 weeks 
- 
Biochemistry*, creatinine* every 2 weeks 
- 
TSH* every 6 weeks 
- 
Blood pregnancy test* for women of childbearing potential every 6 weeks 
- 
Tumor evaluation: The first CT scan or MRI post-baseline must be performed on Day 43, 
but not before 5 weeks after study treatment start, then every 6 weeks up to Month 6 (D204)  
- 
Blood sample collection for immunomonitoring*: on Days 43 and 85 and Month 6 (D204)  
- 
Tumor sample on biopsy: on Day 43 (mandatory) and Day 85 (unless it is unsafe or 
undesirable) for phase Ib and phase II part 1 
- 
Tumor sample on biopsy on Day 85 (mandatory for patients with accessible lesions on Day 
85 for phase II part 2)  
- 
TG4001 SC administration every 2 weeks (phase Ib, phase II part 1 and phase II part 2 
combination arm) 
- 
Avelumab IV infusion every 2 weeks for all patients  
 
From Day 204 until discontinuation of study treatment  
- 
Physical examination* including vital signs, body weight and performance status every 2 
weeks 
- 
Adverse events reporting every 2 weeks 
- 
Concomitant medications and non-drug therapies collection every 2 weeks 
- 
Hematology* every 6 weeks 
- 
Biochemistry*, creatinine* every 6 weeks 
- TSH* every 6 weeks 
- Blood pregnancy test* for women of childbearing potential every 6 weeks 
- TG4001 SC administration every 12 weeks (phase Ib, phase II part 1 and phase II part 2 
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- Avelumab IV infusion every 2 weeks for all patients 
- Tumor evaluation: every 6 weeks up to 9 months then every 12 weeks  
- Blood sample collection for immunomonitoring*: at Month 12 and Month 24 for phase Ib, 
phase II part 1 
- Blood sample collection for immunomonitoring*: at Month 9 (D288) and Month 12 (D372) 
for phase II part 2 
- Tumor sample on biopsy at Month 9 (D288) for phase II part 2 in patients with accessible 
lesions at Month 9  
 
*prior to study treatment(s) administration 
 
Tumor sample on biopsy at the time of progressive disease for phase II part 2 in patients with 
accessible lesions at the time of progressive disease. 
 
 End of treatment visit 
 
This visit should be completed as soon as the patient is discontinued from study treatment. The 
following evaluations will be conducted: 
- 
Clinical evaluation, including vital signs, performance status and body weight 
- 
12-lead Electrocardiogram 
- 
Adverse events reporting 
- 
Concomitant medications and non-drug therapies collection 
- 
Further antineoplastic therapies 
- 
Hematology 
- 
Biochemistry, creatinine 
- 
Free T4, TSH 
- 
Blood pregnancy test for women of childbearing potential 
- 
Tumor sample on biopsy at the time of progressive disease for phase II part 2 in patients 
with accessible lesions at the time of progressive disease 
 
 Safety follow-up visit 
 
This visit should occur 30 days after the last study treatment administration. The following 
evaluations will be conducted: 
- 
Clinical evaluation including vital signs and body weight  
- 
Adverse events reporting  
- 
Concomitant medications and non-drug therapies collection administered within 30 days 
after the last study treatment administration 
- 
Further antineoplastic therapies 
- 
Hematology 
- 
Biochemistry, creatinine 
- 
Blood pregnancy test for women of childbearing potential 
 
 Safety follow-up phone call 
 
At 90 days after the last administration of study treatment, patients will be contacted by 
telephone to collect information on new or ongoing SAEs and treatment-related non-serious 
AEs.  Patients will also be asked about any further antineoplastic therapy. 
 

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 Post-study follow-up 
 
PFS-FU visit: 
For patients who stopped the study treatment for a reason other than progressive disease based 
on RECIST 1.1 (e.g., AE), tumor evaluation should be obtained every 6 weeks until disease 
progression by RECIST 1.1 or for a period of 9 months after the start of study treatment. 
Beyond 9 months, the evaluations will be performed every 12 weeks until disease progression 
by RECIST 1.1. Tumor measurements will be recorded in the eCRF with the date and method 
of tumor assessment and the response evaluation in PFS-FU visit. This follow-up should be 
done even if patients start subsequent antineoplastic therapies.  
Further antineoplastic therapies, given after end of study treatment will be reported in the eCRF 
with the start date and end date. 
Tumor sample on biopsy at the time of progressive disease is to be performed for phase II part 
2 in patients with accessible lesions at the time of progressive disease. 
 
OS-FU: 
From the safety follow-up or last PFS follow-up visit the patient will be followed for survival 
every 3 months until death (phone call is considered as a follow-up) or until the date of last 
contact if the patient is lost to follow-up or withdraws consent for collection of long-term data. 
 
 Biomarkers and Translational Research 
 
As biomarker research is constantly evolving, the selection of markers with the highest 
specificity and relevance to treatment effect may change. 
 
 Immunomonitoring  
 
Blood samples 
 
Blood samples will be collected at baseline, on Day 1, Day 8, Day 43, Day 85, at Month 6, 
Month 12 and Month 24 (prior to study treatment administrations) for phase Ib and phase II 
part 1.  
For phase II part 2 blood samples will be collected at baseline, on Day 1, Day 8, Day 15, Day 
43, Day 85, at Month 6 (D204), Month 9 (D288) and Month 12 (D372) (prior to study treatment 
administrations) and for patients in the combination arm treated with TG4001 on Day 1 6 hours 
post-dose. 
The following samples will be collected to assess: 
Phase Ib and phase II part 1:  
• 
 
 
 
 
 
 
 
 
 
 
 
 

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Phase II part 2:  
• 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
Tumor samples 
 
For phase Ib and phase II part 1 tumor samples will be collected at baseline, on Day 43 and on 
Day 85 (unless it is unsafe or undesirable). Of note, availability of tumor material from fresh 
biopsies will be a prerequisite at baseline for all patients to be enrolled in the study. 
For phase II part 2 and to ensure an adequate number of paired samples to perform meaningful 
analyses to support objectives of translational research patients with accessible lesions should 
undergo biopsy per protocol, i.e. tumor samples will be collected at baseline, and for patients 
under study treatment on Day 85, at Month 9 (D288) and at time of progressive disease.  
 
For cases when an on-treatment biopsy is required but not feasible due to complete response or 
not deemed safe by the investigator, these cases must be clearly documented in the medical 
record. 
 
Tissue collection: Endoscopic biopsies, core needle biopsies, excisional biopsies, punch 
biopsies and surgical specimens are suited. Material from bone biopsies is not suited. Fine 
needle aspiration biopsies are not suited. The most recent biopsy or surgical specimen is 
required. The biopsy or surgical specimen must have been collected within 21 days prior to the 
first IMP administration at baseline, if applicable. 
 
For each biopsy (20 mm 18G biopsies) 3 to 4 tissue fragments will be collected at each 
timepoint.  
 
The following assessment will be considered: 
• 
 
 

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 Handling of biological and tissue samples 
 
Details on the calendar/procedures for handling of samples for immunological tests and tumor 
biomarkers are provided in a separate Manual. 
 
 
8 ASSESSMENT OF EFFICACY 
 
• 
Assessment of efficacy according to RECIST VERSION 1.1  
 
The assessment of efficacy is based on Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 (Eisenhauer E.A. et al., 2009). 
 
For efficacy evaluation, patients must have at least one measurable lesion by CT/MRI scan 
(minimum size not less than 10 mm) at baseline and a post-baseline evaluable CT-scan at week 
6 after start of study treatment with a best overall response assessment different from 
‘Unknown’ according to RECIST evaluation criteria. However, if a patient progressed or died 
due to underlying cancer before scheduled scan 6 weeks after study treatment start could be 
performed, the patient will still be included in the evaluable population.  
Tumor assessment will be performed LOCALLY according to investigator’s assessment every 
6 weeks from the start of study treatment until disease progression or for a period of 9 months 
after start of study treatment, whichever occurs first. Beyond 9 months after start of study 
treatment, the evaluations will be performed every 12 weeks until disease progression. The 
same schedule of tumor evaluation will be applied for patients who stopped the study treatment 
for any reason other than progressive disease. 
For all patients, tumor response assessment will be performed by preferably CT (or MRI) of 
the head and neck, chest, abdomen and all other known sites of disease (e.g. pelvis, if 
applicable) and other established assessments of tumor burden if CT/MRI imaging is 
insufficient for the individual patient. In case of bone pain, an adequate radiological and/or 
isotopical exploration is to be performed to research metastases. All the scans performed at 
baseline and other imaging performed as clinically required (other supportive imaging) need to 
be repeated at subsequent visits.  
Per RECIST, the imaging method used at baseline should be matched at all subsequent 
assessments, but, for a number of reasons such as site error (e.g. switch from MRI to CT) or 
renal dysfunction (making contrast a risk), this will not always be done. A strict implementation 
of RECIST would mean that any change in imaging method compared to one used at baseline 
should lead to unknown overall response at given assessment. However, a change in the use of 
contrast does not necessarily represent a change in precision since for many tumor types, the 
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Therefore, in the calculation of overall response, the methods/modalities listed under the same 
bullet point will be considered the same: 
- 
‘CT with contrast’ and ‘CT without contrast’ 
- 
‘Spiral CT with contrast’ and ‘spiral CT without contrast’ 
- 
‘MRI with contrast’, ‘MRI without contrast’, ‘Dynamic contrast – enhanced MRI’ and ‘GD-
MRI’ 
In rare instances when radiological assessment is not possible to determine the progression 
(e.g., carcinomatous meningitis), other methods may be used (e.g., pathology, cytology). 
 
For patients with a global deterioration of health status requiring discontinuation of study 
treatment without documented progression, every effort should be made to document objective 
progression even after discontinuation of treatment. 
 
For phase Ib and phase II part 1 the duration of observation for efficacy lasts from the date of 
the first study treatment administration to the date of documented progression. 
 
For phase II part 2 the duration of observation for efficacy lasts from the date of randomization 
to the date of documented progression or death whichever occurs first.   
 
Data of locally performed tumor evaluations will be used for efficacy assessment. For phase II 
part 2 and to allow independent central review, anonymized copies of CT/MRI will be collected. 
 
To assess objective response, the tumor burden at baseline will be estimated and used for 
comparison with subsequent measurements. At baseline, tumor lesions will be categorized in 
target and non-target lesions as described in Appendix IV. 
 
Definitions of measurability of lesions and criteria for response are detailed in Appendix IV. 
Results for these evaluations will be recorded with as much specificity as possible so that pre- 
and post-treatment results will provide the best opportunity for evaluating tumor response.  
Any CR or PR should be confirmed as described in Appendix IV. In the case of a PR or CR, a 
confirmatory CT or MRI scan must be done no sooner than 28 days (preferably at the scheduled 
6-week interval).  
 
9 ASSESSMENT OF SAFETY 
 
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. 
 
The safety assessments will be performed according to the schedule of assessment (refer to 
Appendix III). 
 
 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 of the last dose of the study drug, having been absent pre-
treatment or that has worsened relative to the pre-treatment state. Any adverse event deemed 

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related to study drug will also be considered a TEAE regardless of elapsed time since last study 
drug dose. 
 
Adverse Event (AE) 
An AE for the purposes of this protocol is a medical occurrence or deterioration of a pre-existing 
medical condition occurring after signing the informed consent and even if the event is not 
considered to be related to the study treatment(s). 
 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
Adverse reaction (AR): 
All noxious and unintended responses to a medicinal study product (TG4001 or avelumab) 
related to any dose or to a study specific procedure.  
 
Laboratory abnormality 
A laboratory abnormality is reported as an AE if it is out of range, considered by the Investigator 
as clinically significant (i.e. with clinical manifestations or requiring treatment or clinical 
management).  
 
Other significant abnormalities 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non serious or serious AE, 
as appropriate, and reported accordingly. 
 
Other significant adverse events 
Any events and any laboratory abnormalities that led to an intervention, including withdrawal 
/ dose reduction of IMP or significant additional concomitant therapy other than those reported 
as SAE, and that are considered by Transgene or the Investigator to be of special interest 
because of clinical importance. 
Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR) / Suspected Unexpected 
Serious Adverse Reaction (SUSAR): 
Any untoward medical occurrence that at any dose: 
- results in death, 
The death of a patient is not per se an AE but an outcome. “Death” should be considered as 
a SAE only in case of “unexplained death” when no cause is identified. The event that 
resulted in a fatal outcome should be determined and reported as the SAE. 
- is life threatening, 
This term refers to an event in which the patient was at immediate risk of death at the time 
of the event; it does not refer to an event that hypothetically might have caused death if it 
was more severe. 
- requires inpatient hospitalization or prolongation of existing hospitalization, 
The hospitalization is an action taken to treat the event. It should not be reported as a SAE, 
but the AE leading to hospitalization. 
Hospitalization for diagnosis or planned treatment procedures without AE should not be 
reported as a SAE. 
- results in persistent or significant disability/incapacity, 

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The disability is a substantial disruption of a person’s ability to conduct normal life 
functions. 
- is a congenital anomaly/birth defect, 
The “congenital anomaly/birth defect” relates to events occurring to babies born after their 
mother and/or father have taken drug at the time of pregnancy confirmation or during 
pregnancy. 
- is a significant medical event that may not be immediately life threatening or result in death 
or hospitalization, but may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above (example: intensive treatment in an 
emergency room or at home for bronchospasm, convulsions that do not result in 
hospitalization…). Medical and scientific judgement should be exercised in deciding 
whether some events should be considered as serious because their quick reporting to 
Transgene may be of interest for the overall conduct of the study. 
 
Note: 
 
• For SAR and SUSAR there is a reasonable relationship with an investigational medicinal 
product or a study procedure. 
 
The following situations do not need to be reported as SAEs:  
1. Elective hospitalization for pre-existing conditions that have not been exacerbated by trial 
treatment. 
2. A hospitalization which was planned before the patient consented for study participation 
and where admission did not take longer than anticipated. 
3. A hospitalization planned for protocol related treatment or protocol related procedure as 
per institutional standard timelines. 
4. Social and/or convenience admission to a hospital. 
5. Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that leads to 
the procedure is an (S)AE. 
6. Situations where an untoward medical occurrence did not occur (palliative care, 
rehabilitation, overdose without occurrence of an adverse event). 
7. 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. 
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. 
Adverse reactions will be considered as expected, unless nature, severity, specificity, or 
outcome is not consistent with the one previously observed. Adverse reactions with observed 
fatal outcome in the avelumab clinical development programs included: immune-related 
pneumonitis, immune-related hepatitis, immune-related myocarditis, immune-related 
pancreatitis. 
Expected adverse reactions are those listed or characterized in the reference document (i.e. IB).  
Unexpected adverse reactions are those not listed in the reference document or not identified. 
Fatal and life-threatening adverse reactions are always to be reported as unexpected.  
 
Overdose 
Avelumab: 
- 
For an administration at a dose of 10 mg/kg an overdose is defined as any dose ≥ 10% than 
the calculated dose for that particular administration (phase Ib and phase II part 1).  

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- 
For an administration at a flat dose of 800 mg an overdose is defined as any dose above 800 
mg (phase II part 2).  
TG4001: 
- 
 an overdose is an administration at a higher dose than the highest dose already tested (i.e. 
5 x 107 PFU) or higher than the dose planned according to the schedule of administration.  
 
Overdose must not be considered as an AE. However, if the patient experiences an AE/SAE 
related to this overdose, it should be reported as such. 
 
Verbatim 
The terms or the English equivalent of the terms as reported by the Investigator on the eCRF 
pages and on the SAE form to describe an event. 
 
 Time period for collection 
 
The study period during which all Aes and SAEs must be reported begins after informed consent 
is obtained and ends 30 days following the last administration of any study treatment (safety 
follow up visit).  If the safety follow-up visit is performed less than 30 days after the last IMP 
administration, any AE / SAE occurring between the safety follow-up visit until 30 days after 
last study treatment administration will be considered as AE / SAE and notified to Transgene, 
regardless of their relationship to IMP(s). 
 After this period, and until day 90 after last administration of study treatment (i.e. until safety 
follow-up phone call) investigators should report treatment-related non-serious AE and all SAEs. 
Ongoing SAEs at the 90-day safety follow-up phone call must be followed up until stabilization 
or until the outcome is known, unless the patient is documented as “lost to follow up”.  
 
SAEs occurring more than 90 days after administration of the last dose of any study treatments, 
and evaluated by the investigator as related to the IMP(s) should be collected and reported to the 
sponsor indefinitely even after study closure. These will however not be reported in the eCRF 
after Database lock. 
If an Adverse Event occurs during the screening period (i.e., after ICF signature and before start 
of study treatment ), 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., diarrhoea). 
From start of study treatment, AEs will be recorded on an “AE” page. In case of worsening of 
a medical condition which started before start of study treatment, an AE page will be completed 
using a verbatim starting by “worsening of…”. 
 
 Adverse event / Serious adverse event management 
 
 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: 
• nature of the event with self-explanatory and concise medical terminology (if possible 
indicate a diagnosis or syndrome instead of symptoms), 

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• 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 (separate evaluation for TG4001, avelumab), or to study 
procedures, 
• action taken regarding the study treatment (separately for TG4001, avelumab), 
• 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 4.03 dated 14 
June 2010 for phase Ib and phase II part 1, version 5.0 dated 27 November 2017 for phase II 
part 2), 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 in severity category during the course of an adverse event should be reported on 
the AE page of the eCRF with corresponding dates. 
 
Relationship to the IMP(s) 
The relationship to the IMPs (separate evaluation for TG4001 and avelumab) of each AE/SAE 
will be evaluated by the Investigator with the “global introspection” method using the following 
levels: 
● Not related: the temporal relationship of the clinical event to the administration of avelumab 
and TG4001 (separate evaluation) makes a causal relationship unlikely; and other drugs, 
therapeutic interventions or underlying conditions provide a sufficient explanation for the 
observed event. 
● Related: the temporal relationship of the clinical event to the administration of avelumab and 
TG4001 (separate evaluation) makes a causal relationship possible; and other drugs, therapeutic 

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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 drug or 
recurrence upon rechallenge may also be observed. 
 
Outcome 
The outcome is rated as follows: 
- recovered,  
- not recovered, 
- 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 TG4001/avelumab 
Action taken will be provided separately for each study treatment. 
 
- None: 
TG4001/avelumab administration continues as planned in the protocol, or 
has not yet been administered and no action is planned 
- Cancelled: 
TG4001/avelumab administration following the occurrence of the event is 
cancelled 
- Stopped: 
TG4001/avelumab is definitively stopped 
- Not applicable: TG4001/avelumab administration is already stopped 
 
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) 
 
An AE/SAE requiring therapy must be treated with recognized standards of medical care to 
protect the health and well-being of the patient. Any medication or non-drug therapy given will 
be reported on the eCRF pages dedicated to the collection of concomitant medications. 
 
 Follow-up 
 
Once an AE is detected, it must be proactively followed until its resolution or 30 days after the 
last study treatment administration. After this visit and until day 90 after last administration of 
study treatment non-serious treatment-related Aes and all SAEs have to be followed. Ongoing 
SAEs at the 90-day safety follow-up phone call must be followed up until stabilization or until 
the outcome is known, unless the patient is documented as “lost to follow up”. 
In addition, any significant AE as recommended by Transgene must be followed until it is 
resolved or stable or returned to baseline status.  
 

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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) and is thought to be related to the study treatment. 
 
 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 filed in the Investigator Site File along with copies of any 
correspondence with the Independent Ethics Committee (IEC). 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. 
 
 Reporting of DLTs during the phase Ib of the study 
 
During the phase Ib of the study, Transgene must be informed immediately by the center of 
the occurrence of any DLT occurring within the first 4 weeks of study treatments in all 
patients included in the phase Ib of the study.  
 
The following action must be undertaken by the investigators on occurrence of any AE that 
fulfill the criteria for a DLT: 
• The Investigator must inform Transgene and duly complete the appropriate eCRF form 
even if the data are incomplete or if it is obvious that more data will be needed.  
• The following information must be present: description of the AE, intensity and 
relationship to study drugs, date of onset, status at the time of reporting, action taken on 
study treatments. 
• Transgene may request any additional information  (copies of reports, lab tests etc., ) to 
the center in order to better assess the DLT. 
 
 Serious Adverse Event / Serious Adverse Reaction / Suspected Unexpected Serious 
Adverse Reaction notification 
 
Reporting to Transgene 
Any SAE occurring during the course of the study (from the signature of ICF and up to 90 days 
after last study treatment administration whether or not related to the IMP(s) MUST be reported 
to Transgene. The Investigator must complete and fax a “Serious Adverse Event Form” to 
Transgene within a maximum of 24 hours of occurrence or knowledge of the event. 
 
 
France 
Pharmacovigilance Physician  
 
 
 
 
 
 
 
 
 
 
 
An Investigator 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 

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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 IMP(s). The signed form 
must be faxed to Transgene immediately. 
 
The SAE form should 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 initial SAE form by using a 
new “SAE form” with the box “follow-up” ticked and sent to 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 SAE will be followed to resolution or stabilization. 
 
Notification to Regulatory Authorities / Gene Therapy Bodies / Ethics Committee 
Transgene will be solely responsible for regulatory reporting of SUSAR and any other SAEs to 
Regulatory Authorities, IEC(s) / IRB(s) and Gene Therapy Bodies as per local regulations.  
 
Transgene will also be responsible for reporting SAEs to Ethics Committees (Ecs) and 
Investigators in accordance with local regulations/requirements. 
In case of SUSAR, Transgene will inform all investigators involved in any study with TG4001 
that such an event has been reported. 
The Investigator is responsible for informing IRB(s) of SUSARs, any other SAEs and any 
follow-up information as per local regulations. 
Transgene 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). 
Transgene will transmit SAEs to Merck KgaA and Pfizer for all initial or follow-up reports and 
any safety information originating from this Study within the timelines and formats specified 
in and in accordance with the Safety Data Exchange Agreement. 
Merck KgaA / EMD Serono and Pfizer will each cross-report SUSARs from the Study 
associated with avelumab to national Regulatory Authorities of countries where they are 
Sponsors of clinical trials with avelumab and where such cross-reporting is required per 
applicable regulations. 
 Special situations 
 
Any clinical AE with severity of Grade 4 must be reported as an SAE; however, a laboratory 
abnormality of Grade 4, such as anemia or neutropenia, is considered serious only if the 
condition meets one of the serious criteria described above (see Section 9.1). 
 
Pregnancy 
Study treatments must be discontinued immediately when a patient becomes pregnant. 

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The occurrence of a pregnancy must be reported to Transgene by the Investigator using a 
“Pregnancy form”: 
• The first part of the form is used to collect information at the beginning of the pregnancy. It 
should be completed and reported as soon as possible and within 24 hours of knowledge 
• The second part of the form is to collect information about the outcome of the pregnancy. It 
should be reported within the same time frame and even if the patient was withdrawn from 
the study 
 
Pregnancies have to be followed up to the completion or termination of the pregnancy, 
collecting information about the pregnancy and knowledge of the new-born medical status. 
Pregnancy outcomes must be collected for the female partners of any males who took the 
IMP(s). Consent to report information regarding these pregnancy outcomes should be obtained 
from the mother. 
 
Pregnancy itself is not considered as an AE. However, any problem met during the pregnancy 
should be reported as an AE or a SAE. Spontaneous or induced abortions as well as ectopic 
pregnancy should be considered as serious. Similarly, any congenital anomaly/birth defect in a 
child born to a female patient exposed to avelumab and/or TG4001 should be reported as an 
SAE. 
The time period for collecting new pregnancies is from the first administration of the IMP(s) 
up to 3 months after the last study treatment administration. 
 
Overdose 
Any overdose should be reported to Transgene, and documented and followed-up using an 
“Overdose form”. In addition, any associated symptoms should be reported as an AE or SAE. 
 
 Laboratory values, vital signs, physical findings and other safety data 
 
Laboratory tests results will be recorded on the laboratory results Forms of the eCRF. 
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 in 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 treatments (e.g. cancellation or permanent discontinuation) 
• requiring corrective treatment or clinical management 
Clinically relevant abnormal laboratory or tests results will be reported by the Investigator and 
followed until normal or stabilization, or the safety follow-up visit if they are not related to 
study treatments. They should be recorded on the AE eCRF pages under the signs, symptoms, 
or diagnosis associated with them. 
 
Clinically relevant abnormal findings in vital signs measurements or physical examinations or 
ECGs will be reported as Aes or SAEs by the Investigator. 
 
10 STATISTICAL METHODS PLANNED AND SAMPLE SIZE 
 
 Data sets analyzed 
 

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Safety population (SAF): all patients included and who received any amount of study treatment 
will be included in the SAF. Any patient who is assigned a patient number, but does not receive 
any study treatment will not be included in the SAF. 
 
Evaluable patients’ population for DLT determination (DLT population): For the phase Ib of 
the study, the purpose being to evaluate the safety of the combination, patients must complete 
the first 4 weeks of the combination or discontinue before the end of the 4 weeks for a DLT to 
be evaluable for the primary objective of the phase Ib of the study. Patients who are not 
evaluable for phase Ib safety analysis or are withdrawn for other reasons than toxicity, will be 
replaced.  
Patients must receive at least one dose of both IMPs (TG4001 + avelumab) and have at least 
one valid post-baseline safety assessment. The statement that a patient had no AE, on the 
Adverse Events eCRF page, constitutes a valid safety assessment. The occurrence of death also 
constitutes a valid safety assessment.  
 
Phase II part 1: Evaluable patients’ population for tumor response (evaluable per protocol 
population, EPP): consists of all included patients who were dosed with both IMPs (TG4001 + 
avelumab) and have at least one baseline and one post-baseline evaluable CT-scan at week 6 
after start of study treatment with a best overall response assessment different from ‘Unknown’ 
according to RECIST 1.1 evaluation criteria. However, if a patient progressed or died due to 
underlying cancer before scheduled scan 6 weeks after study treatment start could be performed, 
the patient will still be included in the evaluable population. Any patient who has a major 
inclusion/exclusion violation, major dosing violation, or major protocol conduct violation will 
be excluded from the EPP. Major dosing violation is considered when minimum exposure is 
not met defined as at least 6 TG4001 injections and 3 avelumab administrations except if patient 
has progressed or died due to underlying disease before or at the first evaluation. Due to 
potential abscopal effect when associating radiotherapy and immunotherapy, patients receiving 
palliative radiotherapy will be analyzed separately. Whatever the reason for withdrawal, except 
for disease progression and death due to underlying cancer before scheduled scan 6 weeks after 
study treatment start could be performed, patients considered as non-evaluable for tumor 
response will be replaced.  
  
Phase II part 2: Full Set Analysis (FAS) will be the primary set for efficacy analyses. It consists 
of all randomized patients who were administered at least one dose of IMP(s) according to the 
treatment allocated at randomization.  
Evaluable patients’ population per protocol (evaluable per protocol population, EPP): consists 
of all patients from the FAS without any major inclusion/exclusion violation, major dosing 
violation as defined for phase II part 1, or major protocol conduct violation who were dosed 
with IMP(s) according to the treatment allocated at randomization and have at least one baseline 
and one post-baseline evaluable CT-scan at week 6 after start of study treatment with a best 
overall response assessment different from ‘Unknown’ according to RECIST 1.1 evaluation 
criteria.  
 
 Determination of sample size 
 
In the phase Ib part of the study, 3 to 6 evaluable patients will be included and treated at each 
selected dose level. Should the results of this first part of the study show an acceptable safety 
profile of the combination, accrual in the phase II part of the study will start. 
 

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Phase II part 1: A Simon’s two-stage design was used. The null hypothesis for response rate 
(H0) is set at 10%, corresponding to the response rate observed in second line patients, the 
alternative hypothesis of efficacy is set at HA = 25%, the type I error α is set at 5%, the type II 
error β is set at 20% (power = 80%). Under these hypotheses and applying a Minimax two-
stage Simon design, enough patients will be treated to obtain 22 evaluable patients in the first 
stage. If at least 3/22 patients are considered responders, the enrolment will be continued, 
otherwise it will be stopped. In the initial design and at the second stage enough patients should 
have been treated to obtain at least 40 evaluable patients in total. The study would have been 
considered positive with at least 8/40 responders. With a hierarchical strategy on the final 
analysis, a subgroup analysis performed in oropharyngeal SCCHN patients and with a null 
hypothesis for response rate (H0) set at 10% and the alternative hypothesis of efficacy set at 
HA = 35%, 18 oropharyngeal SCCHN patients would have been needed to reach a power of 
81% and actual alpha at 2.8%. This analysis would have been considered positive with at least 
5 responders among the 18 SCCHN patients. The second stage of the Simon’s design has not 
been done following the decision to exclude oropharyngeal SCCHN and to change to a 
randomized controlled two-arms study (phase II part 2).   
The final ORR analysis will be performed 24 weeks after last patient-in. 
 
Phase II part 2: 
The primary objective is to compare the PFS of TG4001 in combination with avelumab vs 
avelumab alone in patients with R/M HPV-16 positive advanced malignancies and without liver 
metastases at baseline. PFS will be evaluated based on RECIST 1.1. 
 
Patients without liver metastases at baseline: 
Efficacy will be evaluated by comparing the PFS between monotreatment arm (avelumab alone) 
and combination arm (TG4001 and avelumab) with an adaptive approach.
 
 
 
 
 
 
With an one-sided type I error α at 5%, 76 events are needed to reach a power of 95%. This 
should happen after around 80 patients enrolled (40 patients per arm). Assuming 5% drop-out 
in each arm, 84 patients will be randomized.   
 
Due to the uncertainty on the true treatment effect and data variability, and to reduce the risk of 
running an underpowered study, it is considered appropriate to adopt an adaptive approach for 
the sample size. This will offer a mechanism to adjust the sample size in response to treatment 
effect and variability estimates seen at a planned interim analysis.  
 
The interim analysis will be conducted after 37 events which will occur approximately 16 
months after the inclusion of the first patient. At that time, it is estimated to have around 50 
patients enrolled. Based on the results of the interim analysis, sample size re-estimation will be 
performed. According to simulations on CHW (Cui, Hung and Wand) approach using EAST 
6.5., the proposal is as follows:  
• Start with a fixed sample size calculation based on the primary endpoint. 
• Based on the interim analysis result maintain or increase the sample size in order to 
obtain the desired power of 90%.  

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Conditional power will be calculated based on the interim results. Should the conditional power 
be in the favorable or unfavorable range the sample size and the number of events will not be 
adjusted and will remain at the initial sample size. Conditional power falling into the promising 
zone will have a sample and events increase. The regions and their implications on sample size 
are detailed below:  
 
- 
Favorable: If the interim results are sufficiently favorable corresponding to a CP of 
more than 90%, final analysis will be performed on 74 PFS events corresponding to an 
estimated sample size of 80 evaluable patients. This will occur approximately 26 months 
after the inclusion of the first patient. 
 
- 
Promising zone: If the interim results are equivalent to a CP between 90% and 30%, 
the sample size will be recalculated according to the median PFS observed in the two 
arms with a cap of 2 times the initial events.   
 
 
- 
Unfavorable zone: If the interim results are not favorable corresponding to a CP 
between 30% and 10%, the trial may continue up to the initial sample size of 80 patients 
or could be stopped 
 
 
- 
Futility: If the interim results are futile corresponding to a CP lower than 10%, the trial 
will be stopped for futility at the interim analysis. 
 
 
 
 
Assuming an uniform enrollment with 3 patients per month and based on simulations, in case 
of sample size reassessment, an average of 124 events would be needed (corresponding to 136 
patients). Assuming a 5% lost to follow-up or withdrawal of consent rate, a total of 142 patients 
should be randomized to the 2 treatment arms in a 1:1 ratio (71 patients in each treatment arm). 
Based on the aforementioned assumptions, a power of 70% is expected using an unstratified 
log-rank test at a 1-sided cumulative 5% level of significance. 
 
 
 
 
 
 
 

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Full details of the adaptive method for sample size specified above will be given in the 
Statistical Analysis Plan (SAP). 
 
Patients with liver metastases at baseline: 
 
A sample size of 
 is planned. 
 
 
 
 
 
 
 
 Study endpoints 
 
 Primary endpoint 
 
Phase Ib: Dose limiting toxicities defined as follows: 
- 
Grade ≥ 3 drug related adverse event. However, fatigue, nausea/vomiting adequately 
treated with anti-emetics, endocrinopathies adequately controlled with one 
physiologic hormone replacement, skin toxicity and single laboratory values out of 
normal range without any clinical correlate, asymptomatic grade ≥3 lipase or 
amylase elevation, tumor flare defined as local pain, irritation, or rash localized at 
sites of known or suspected tumor or a transient Grade 3 infusion adverse event are 
excluded 
- 
Liver function test abnormality:  
o AST or ALT > 5 x ULN 
o Total bilirubin > 3 x ULN 
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN  
- 
Drug related adverse event requiring treatment interruption for more than 2 weeks 
 
The RP2D will be defined as the dose at which less than 33% of the patients (0 or 1 patient 
among 6 evaluable patients) experience a DLT. 
 
Dose limiting toxicities will be assessed during the first 4 weeks of the combination and will 
be graded according to NCI CTCAE version 4.03. 
 
To be evaluable for the primary objective of the phase Ib of the study, patients must complete 
the first 4 weeks of the combination or discontinue before the end of the 4 weeks for a DLT. 
Patients must receive at least one dose of both IMPs (TG4001 + avelumab) and have at least 
one valid post-baseline safety assessment. The statement that a patient had no AE, on the 
Adverse Events eCRF page, constitutes a valid safety assessment. The occurrence of death also 
constitutes a valid safety assessment. Patients who are not evaluable for phase Ib safety analysis 
or are withdrawn for other reasons than toxicity, will be replaced.  
The DLT population will be the primary population for analyses. These analyses will be 
repeated on the SAF. 
 
Phase II part 1: The primary endpoint of the phase II part 1 is the Overall Response Rate (ORR 
by RECIST 1.1 criteria).  

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The EPP will be the primary population for efficacy analyses in the phase II part 1. These 
analyses will be repeated on the SAF. 
The best response will be recorded from the first study drug administration until documented 
disease progression. A PR or CR must be confirmed at a subsequent evaluation at least 4 weeks 
apart. 
 
Phase II part 2: The primary endpoint of phase II part 2 is PFS by RECISIT 1.1 criteria. The 
FAS will be the primary population for efficacy analyses in the phase II part 2. These analyses 
will be repeated on the EPP.  
 
Progression Free Survival (PFS) is defined as the time from the date of randomization to the 
date of first documented tumor progression or death due to any cause, whichever occurs first. 
If a patient has not had a PFS event at the cut-off date for analysis or at the date when a further 
antineoplastic therapy (other than those planned as study treatment in the protocol) is started, 
PFS will be censored at the date of last evaluable tumor assessment before the cut-off or start 
of further antineoplastic therapy. 
 
 Secondary endpoints 
 
The endpoints for secondary objectives of the study are defined as follows: 
▪ Overall Response Rate (ORR) by using RECIST 1.1 (phase Ib, phase II part 2) 
▪ Progression Free Survival (PFS) (phase Ib, Phase II part 1): time from the date of first 
study treatment administration to the date of first documented tumor progression or 
death due to any cause, whichever occurs first. If a patient has not had a PFS event at 
the cut-off date for analysis or at the date when a further antineoplastic therapy (other 
than those planned as study treatment in the protocol) is started, PFS will be censored 
at the date of last evaluable tumor assessment before the cut-off or start of further 
antineoplastic therapy. 
▪ Overall Survival (OS):  
▪ phase Ib and phase II part 1: time from the date of first study treatment administration 
to the date of death due to any cause. If a patient is not known to have died at the cut-
off date for analysis, survival will be censored at the date of last contact. 
▪ Phase II part 2: time from the date of randomization to the date of death due to any 
cause. If a patient is not known to have died at the cut-off date for analysis, survival will 
be censored at the date of last contact. 
▪ Duration of overall Response (DoR): applies only to patients whose best overall 
response is CR or PR. The start date is the date of first documented response (CR or 
PR) and the end date is the date of first documented disease progression or death, 
whichever occurs first. If no progression has been observed at the cut-off date of 
analysis or at the date when a further antineoplastic therapy is started, DoR will be 
censored at the date of the last evaluable tumor assessment before the cut-off or start of 
further antineoplastic therapy. 
▪ Disease control rate (DCR): proportion of patients whose best overall response is either 
CR, PR, or SD. 
• Percentage of patients with liver metastases at baseline who have disease progression at 
D43 (phase II part 2) 
▪ Safety: the assessment of safety of the combination will be based mainly on the 
frequency of Aes, SAEs, and on the number of laboratory values that fall outside of 

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predetermined ranges. Other safety data (e.g., ECG, vital signs) will be considered as 
appropriate. 
 
 Exploratory endpoints (phase Ib and II) 
 
• To assess the following blood-based parameters and their impact on clinical outcomes 
(baseline and on-treatment sampling):  
• Memory and naïve T cells, regulatory T cells, CD8+ T cells, B cells, NK cells, and 
activation thereof 
• TG4001 and HPV-16-specific and tumor specific humoral and cellular immune 
responses 
• Immune related soluble factors and cytokines 
• To assess tumor-based proteins and RNAs expression with potential prognostic and/or 
predictive value on efficacy outcomes including PD-L1 expression as well as new 
biomarkers identified by transcriptomic analysis (biopsies at baseline, on-treatment and at 
progressive disease) 
• To assess the level of tumor infiltrating lymphocytes (TILs) and phenotypic characteristics 
thereof (biopsies at baseline, on-treatment and at progressive disease) 
• To assess tumor mutation load and describe its impact on clinical outcomes (biopsies at 
baseline, on-treatment and at progressive disease) 
• To assess viral clearance 
 
 Statistical and analytical plans 
 
 Safety analyses 
 
All safety analyses will be performed and summarized in the SAF. 
 
Adverse Events 
AE summaries will include all AEs starting on or after start of study treatment  or that has 
worsened on or after start of study treatment and starting no later than 90 days after the date of 
last study treatment administration.  
All Aes, significant Aes, Aes leading to discontinuation of study treatment (overall and by 
component: TG4001, avelumab), 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, also referred as CTCAE), relationship to study treatment (TG4001 
and/or avelumab). 
Separate AE summaries will be presented by SOC, PT, and CTCAE grade. In the summaries 
presented by grade, all Aes will be pooled. Specific tables will summarize related Aes to IMP 
and Aes of specific interest (injection site reactions). 
The frequency of CTCAE Grade 3 and 4 Aes will be summarized separately. 
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. 
 
Fatal Events 

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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 Informed 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 no later than 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 4.03 for phase 
Ib and phase II part 1, version 5.0 for phase II part 2). 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 plan. Note that for parameters 
with two directions abnormalities (hypo/hyper), two tables will be presented. Laboratory 
abnormalities 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. 
 
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 
 
The analysis of the efficacy endpoints will be performed on the EPP and repeated on the SAF. 
The analysis of efficacy will be based on RECIST 1.1.  
 
• 
Overall Response Rate (ORR) 
Overall response rate (ORR) is defined as the proportion of patients whose best overall response 
is either CR or PR according to RECIST version 1.1. Proportions of patients with a best overall 
response of CR or PR will be presented along with exact 95% confidence intervals. Patients 
with best overall response ‘unknown’ will be summarized by reason for having unknown status.  
Phase II part 2: ORR will be compared between the 2 treatment arms using a (two-sided) 95% 
CI for the difference in proportion of patients whose best overall response is either CR or PR, 
stratified by indication using Cochran-Mantel-Haenszel Chi-Square test. 
 
• 
Progression Free Survival (PFS) 
Phase Ib and phase II part 1: PFS (in months) is defined as the time from the date of first study 
treatment administration to the date of first documented tumor progression or death due to any 

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cause, whichever occurs first. PFS will be censored if no progression or death is observed at 
the cut-off date for analysis, or at the date when a further antineoplastic therapy is started. The 
censoring date will be the date of the last evaluable tumor assessment before the cut-off date or 
start of further antineoplastic therapy. 
Phase II part 2: PFS (in months) is defined as the time from the date of randomization to the 
date of first documented tumor progression or death due to any cause, whichever occurs first. 
PFS will be censored if no progression or death is observed at the cut-off date for analysis, or 
at the date when a further antineoplastic therapy is started. The censoring date will be the date 
of the last evaluable tumor assessment before the cut-off date or start of further antineoplastic 
therapy. The primary analysis will be a comparison of PFS between the 2 treatment arms using 
an unstratified log rank test  at the one-sided 5% level in the FAS. A stratified log rank test 
stratified by indication will be also performed as supportive analysis. 
 
 
HR (together with associated 95% CI) resulting 
from the stratified and unstratified Cox model will also be presented.  
 
PFS will be presented descriptively using Kaplan-Meier curves. Summary statistics from the 
Kaplan-Meier distributions will be determined. 
 
 
• Duration of Overall Response (in case of CR or PR) 
Duration of overall response in months (DoR) applies only to patients whose best overall 
response is CR or PR. The start date is the date of first documented response (CR or PR) and 
the end date is the date of event defined as first documented disease progression or death due 
to underlying cancer. 
DoR will be censored if progression or death due to underlying cancer is not observed at the 
cut-off date for the analysis or start of further antineoplastic therapy. The censoring date will 
be the date of the last evaluable tumor assessment. Kaplan-Meier curves of DoR will be 
constructed. Summary statistics from the Kaplan-Meier distributions will be determined. 
 
• 
Disease Control Rate (DCR) 
Disease control rate (DCR) is defined as the proportion of patients whose best overall response 
is either CR, PR, or stable disease (SD). 
 
• 
Overall Survival (OS) 
Phase Ib and phase II part 1: OS is defined as the time from the date of first study treatment 
administration to the date of death due to any cause. If a patient is not known to have died, 
survival will be censored at the date of last contact.   
 
Phase II part 2: OS is defined as the time from the date of randomization to the date of death 
due to any cause. If a patient is not known to have died, survival will be censored at the date of 
last contact. OS will be presented descriptively using Kaplan-Meier curves. Summary statistics 
from the Kaplan-Meier distributions will be determined. OS will be compared between the 2 
treatment arms using an unstratified log rank test and log-rank stratified by indication at the 
one-sided 5% level in the FAS. 
 
 
HR (together with associated 95% CI) resulting from the stratified and unstratified Cox model 
will also be presented. 
 

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• 
Phase II part 2: Percentage of patients with liver metastases at baseline who have 
disease progression at D43  
 
 
 
 
 
 Biomarkers  
 
Continuous variables may be further classified into categorical variables using quartiles, normal 
ranges, or limit of detection as appropriate. Student’s t test or analysis of variance will be used 
when appropriate. Data will be transformed (e.g., logarithms) prior to analysis if transformation 
is needed to meet the assumptions of normality and homogeneity of variances that underlie 
these methods. Non-parametric methods, such as the Wilcoxon-Mann-Whitney test, will be 
used if data fail to meet these assumptions even after transformation. 
For discrete parameters, statistical analysis may include Chi square tests or Fishers Exact test 
as appropriate. OS and PFS will be analyzed using Cox regression model. Logistic regression 
models will be used to analyze overall responses. Mixed models will be used when appropriate 
for longitudinal analyses. 
In order to explore or discover potentially important relationships between various markers, 
other exploratory statistical methods may be used. 
 
 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 exact (binomial) 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.   
 
For phase Ib and phase II part 1: 
The disposition data will be presented by patient in data listings and in a summary table on:  
- 
Number of patients included (SAF) 
- 
Number of patients included in each population: DLT population, EPP 
- 
Number of patients excluded from the populations and reasons for exclusion 
- 
Number of patients who received the combination 
- 
Number of patients who discontinued TG4001 only and reasons for discontinuation 
- 
Number of patients who discontinued avelumab and reasons for discontinuation 
 
For phase II part 2: 

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- 
The disposition data will be presented by patient and treatment arm in data listings and the 
following items will be presented by treatment arm in a summary table on the FAS: 
- 
Number of patients included (FAS) 
- 
Number of patients included in each population: SAF, EPP 
- 
Number of patients excluded from the populations and reasons for exclusion for each 
population  
- 
Number of patients treated (TG4001 and/or avelumab) 
- 
Number of patients who received TG4001 and avelumab 
- 
Number of patients who discontinued TG4001 only and reasons for discontinuation 
- 
Number of patients who discontinued avelumab and reasons for discontinuation 
 
 Demographic and baseline characteristics 
 
Baseline demographics and patient and disease characteristics data will be listed and 
summarized. Qualitative data (e.g., gender, PS) will be summarized by means of contingency 
tables, and quantitative data (e.g., age and body weight) will be summarized by appropriate 
descriptive statistics (mean, standard deviation, median, minimum, and maximum). 
Summaries will be provided overall for the SAF, the FAS for phase II part 2 and for key 
subpopulations, i.e. DLT population and EPP.   
 
 Treatments 
 
10.5.4.1. 
Prior anti-cancer therapies 
 
Prior antineoplastic therapies will be listed and summarized (surgery, radiotherapy, 
chemotherapy). 
 
The SAF set and the FAS for phase II part 2 will be used for all summaries and listings of prior 
anti-cancer therapies. 
 
10.5.4.2. 
Study treatments 
 
Exposure to TG4001 will be provided by listing and summarizing the number of injections and 
the duration of treatment. 
Exposure to avelumab will be provided by listing and summarizing the number of infusions, 
the cumulated dose and the duration of treatment. 
The SAF and the FAS for phase II part 2 will be used for all summaries and listings of study 
treatment. 
The number of patients with dose omission will be presented by study treatment component, 
along with reasons for the dose omission.  
 
10.5.4.3. 
Concomitant medications 
 
Medications and/or non drug therapies taken by the patient during the month prior to start of 
the study treatment, (continuing or not at the 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. 

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The concomitant medications (i.e., ongoing at the start of study treatment or taken during the 
course of the study) will be coded using the WHO Drug Dictionary and will be listed and 
summarized by active ingredient by means of frequency counts and percentages. 
The SAF and the FAS for phase II part 2 will be used for all above mentioned concomitant 
medication tables. 
 
10.5.4.4. 
Further antineoplastic therapies 
 
All further antineoplastic therapies given after discontinuation of study will be collected with 
their start date and end date. They will be coded using the latest WHO Drug Dictionary and 
listed and summarized by active ingredient by means of frequency counts and percentages using 
the SAF population and the FAS for phase II part 2.  
 
 Protocol deviations 
 
Protocol deviations impacting statistical analyses will be described in the statistical analysis 
plan in order to determine the EPP. A Data Review Meeting will be organized prior to final 
statistical analysis. 
 
11 CHANGES IN THE CONDUCT OF THE STUDY 
 
 Protocol amendments 
 
Changes to this protocol will be effected through amendments issued by Transgene after mutual 
agreement of the Investigator(s) and Transgene. Both the Investigator(s) and Transgene will 
sign the amendments. When applicable, amendments are submitted to Health Authorities and 
the Independent Ethics Committee(s) (IEC(s)) and any other committee(s) 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 committee(s) as locally required for authorisation 
/ approval. 
 
 Premature termination or suspension of the study 
 
The study may be suspended or terminated under any of the following circumstances: 
• Sponsor’s decision 
• Health Authorities’ decision 
• IDMC recommendation in case of a safety concern. However, in this latter case, the final 
decision as to whether or not continue the study will be taken by the Sponsor 
 
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 

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Authorities and the IEC(s) and any other committee(s) 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. 
 
12 ETHICAL CONSIDERATIONS 
 
 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 a written authorization / 
approval and the list of members having participated in the meeting including their 
qualification. 
 
In addition, IEC written approval must be obtained by Transgene for protocol amendment as 
described in Section 9.1 
 
 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 and images collected for this study 
will be stored in a computer database, with confidentiality maintained in accordance with 
national data legislation and the European General Data Protection Regulation for European 
countries. All data computer processed will be identified by patient initials depending on local 
laws) and number only.  
 
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-

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related procedure, including screening tests for eligibility. Any new version of the ICF will be 
signed by all ongoing patients. 
 
Should a patient start with the study treatment more than one month after having signed the 
informed consent form, whatever the reason, it would be ethical to ask him/her to reconfirm 
his/her willingness to participate to the study by signing a new consent form. 
 
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. 
 
 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 
its representative, patients should not be identified by their names, but by an identification code 
system. 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) or the HIPAA 
regulations.  
 
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. 
 
13 REGULATORY CONSIDERATIONS 
 
 Regulatory considerations 
 
This study will be conducted in accordance with: 
- The updated Declaration of Helsinki adopted by the World Medical Association, 
- The ICH (International Conference on Harmonization) Good Clinical Practice R2 (GCP) 
guidelines, and 
- The local regulatory requirements. 
- 
As per the HIPAA regulations, the individual institution may require that the Informed 
Consent and/or HIPAA Acknowledgement/Authorization Form be reviewed by their 
Privacy Board (per HIPAA guidelines). In the instance of a Privacy Board review, approval 
must 
be 
received 
on 
the 
Informed 
Consent 
Form 
and 
Subject 
Acknowledgment/Authorization Form prior to initiating any study related procedures. 
 
 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 and viral safety 
committees, as required. All approvals must be obtained before a patient is exposed to a study-
related procedure, including baseline screening tests for eligibility. 
 

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 Investigators’ obligations 
 
Before the study starts, the Investigator shall provide Transgene with his/her curriculum vitae 
(CV) 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, GCP 
and local regulations. Investigator must ensure that the study has been authorized / approved 
by all Regulatory Authorities, IEC/IRB 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. 
 
The principal investigator, or person designated by the principal investigator, should 
communicate any deviation from the approved protocol to the monitor.  
 
If the principal investigator is aware of the occurrence, or the potential occurrence of a deviation 
that is likely to affect, or affects, the safety and rights of a subject or the reliability and 
robustness of the data generated in the clinical trial (major deviation or serious breach), it should 
be promptly reported to TRANSGENE via the following email address, in order for 
TRANSGENE to meet the legal obligations: 
 
 
 Insurance 
 
Transgene certifies having taken out a civil liability insurance policy covering liability with 
regard to the participants in this study.  
 
14 QUALITY CONTROL AND QUALITY ASSURANCE 
 
 On site monitoring 
 
The monitor will contact and visit the Investigator periodically to evaluate study progress and 
protocol compliance.  
On site monitoring activities are based on instructions given within the Monitoring Plan. 
 
The Investigator and any study staff member will co-operate with the monitor to ensure that 
any problems are resolved. 
 

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 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. 
The sponsor is responsible for making sure that both his representatives (monitor, clinical 
research associate) 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 investigation site or the sponsor 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. 
Investigators are reminded that the Investigator Site File must be kept up to date due to possible 
unannounced inspections.  
 
15 DATA HANDLING AND RECORD KEEPING 
 
 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 treatments (TG4001, avelumab) administrations, concomitant medications, evaluation 
criteria and nature of adverse events with date of start and end and relationship to study 
treatments. The location of each source data will be identified on a dedicated form. 
 
If computerised 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 authorised 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, 
➢ 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: 
o the log in and password are entered upon signature 

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o 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. 
 
 Case report forms 
 
Electronic Data Capture (EDC) will be used for this study, meaning that all eCRF 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 or designee and signed 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 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 confirmations 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 data for 
archiving at the investigational site. 
 
16 CLINICAL STUDY REPORT AND PUBLICATION 
 
 Clinical study report 
 
All relevant data will be reported in a clinical study report which will be prepared by 
Transgene/ESP and submitted for comments and signature to the coordinating / principal 
Investigator. The final report is used for regulatory purposes by Transgene according to local 
regulations and provided to each Investigator once finalized. 
 
 Confidentiality of study data 
 
Any information provided by Transgene, including non clinical data, protocols, eCRFs, verbal 
and written information, and results of the study will be kept strictly confidential and confined 

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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.  
 
 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 the sponsor 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 the sponsor’s personnel exceeded that of conventional monitoring 
will be considered for co-authorship provided all other criteria of ICMJE are met.  
 
17 ARCHIVING 
 
 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. 
 
 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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REFERENCES 
 
Adams S., Gray R.J., Demaria S., Goldstein L., Perez E.A., Shulman L.N., Martino S., Wang M., Jones V.E., 
Saphner T.J., Wolff A.C., Wood W.C., Davidson N.E., Sledge G.W., Sparano J.A. and Badve S.S. 
"Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III 
randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199." J Clin Oncol. (2014) 32(27): 
2959-2966. 
 
Aggarwal C., Heisler L.M., Saba N.F., Algazi A.P., Sukari A., Seiwert T., Haigentz M., Porosnicu M., Bonomi 
M., J. Boyer J., Durham N., Kumar R., Laubscher K., Gong M., Ceaicovscaia N. and Gascó Hernández 
A. Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus 
Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. ESMO VIRTUAL 
CONGRESS.(2020). 
 
Ahomadegbe J.C., Barrois M., Fogel S., Le Bihan M.L., Douc-Rasy S., Duvillard P., Armand J.P. and Riou G. 
"High incidence of p53 alterations (mutation, deletion, overexpression) in head and neck primary tumors 
and metastases; absence of correlation with clinical outcome. Frequent protein overexpression in normal 
epithelium and in early non-invasive lesions." Oncogene. (1995) 10(6): 1217-1227. 
 
Alhamarneh O., Amarnath S.M., Stafford N.D. and Greenman J. "Regulatory T cells: what role do they play in 
antitumor immunity in patients with head and neck cancer?" Head Neck. (2008) 30(2): 251-261. 
 
Andrade P., Deleo A., Visus C., Butterfield L., Argiris A. and Ferris R.L. "Phase I adjuvant trial of multi-epitope 
p53 vaccine for patients with squamous cell carcinoma of the head and neck (SCCHN): A preliminary 
report." J Clin Oncol 27:15s, 2009 (suppl; abstr 3012). (2009). 
 
Antoine G., Scheiflinger F., Dorner F. and Falkner F. "The complete genomic sequence of the modified Vaccinia 
Ankara Strain: Comparison with other Orthopoxviruses." Virology. (1998) 244: 365-396. 
 
Attner P., Du J., Nasman A., Hammarstedt L., Ramqvist T., Lindholm J., Marklund L., Dalianis T. and Munck-
Wikland E. "The role of human papillomavirus in the increased incidence of base of tongue cancer." Int 
J Cancer. (2010) 126(12): 2879-2884. 
 
Balloul J.M. "Development of a highly -attenuated vaccinia virus co-expressing the E6 and E7 genes of Human 
Papillomavirus type 16 and the human IL-2 gene." Study Report (DP0037) Transgene, Strasbourg, (1998) 
 
Balloul J.M. and Pecheur C. "Comparison of IP versus SC vaccination protocols with recombinant vaccinia viruses 
(MVA) expressing genes of HPV16 in a HPV + mouse tumor model." Study Report (DP0107) Strasbourg, 
Transgene, (2006) 
 
Balloul J.M. and Pecheur C. "Immunotherapy experiment with a recombinant vaccinia virus expressing genes of 
HPV16 in a mouse model of cervical cancer: definition of the dose number for optimal 
immunotherapeutic effect." Study Report (DP0108) Strasbourg, Transgene, (2007) 
 
Bizouarne N. "Comparison of recombinant vaccinia viruses expressing early genes of HPV16 in a mouse model 
of cervical cancer. Study of the immunization route in an immunoprophylaxis experiment." Study Report 
(DP0046) Transgene, Strasbourg, (1998a) 
 
Bizouarne N. "Study of the efficiency of MVA8042 in a mouse model of cervical cancer. Dose effect in an 
immunoprophylaxis experiment." Study Report (DP0048) Transgene, Strasbourg, (1998b) 
 
Braakhuis B.J., Snijders P.J., Keune W.J., Meijer C.J., Ruijter-Schippers H.J., Leemans C.R. and Brakenhoff R.H. 
"Genetic patterns in head and neck cancers that contain or lack transcriptionally active human 
papillomavirus." J Natl Cancer Inst. (2004) 96(13): 998-1006. 
 

Transgene / Confidential 
Study Protocol TG4001.12 
Final Version 10.0 – 06 December 2023 
Page 124/160 
 
Brachman D.G., Graves D., Vokes E., Beckett M., Haraf D., Montag A., Dunphy E., Mick R., Yandell D. and 
Weichselbaum R.R. "Occurrence of p53 gene deletions and human papilloma virus infection in human 
head and neck cancer." Cancer Res. (1992) 52(17): 4832-4836. 
 
Brahmer J.R., Tykodi S.S., Chow L.Q., Hwu W.J., Topalian S.L., Hwu P., Drake C.G., Camacho L.H., Kauh J., 
Odunsi K., Pitot H.C., Hamid O., Bhatia S., Martins R., Eaton K., Chen S., Salay T.M., Alaparthy S., 
Grosso J.F., Korman A.J., Parker S.M., Agrawal S., Goldberg S.M., Pardoll D.M., Gupta A. and 
Wigginton J.M. "Safety and activity of anti-PD-L1 antibody in patients with advanced cancer." N Engl J 
Med. (2012) 366(26): 2455-2465. 
 
Bray F., Sankila R., Ferlay J. and Parkin D.M. "Estimates of cancer incidence and mortality in Europe in 1995." 
Eur J Cancer. (2002) 38(1): 99-166. 
 
Brun J.L., Dalstein V., Leveque J., Mathevet P., Raulic P., Baldauf J.J., Scholl S., Huynh B., Douvier S., 
Riethmuller D., Clavel C., Birembaut P., Calenda V., Baudin M. and Bory J.P. "Regression of high-grade 
cervical intraepithelial neoplasia with TG4001 targeted immunotherapy." Am J Obstet Gynecol. (2011) 
204(2): 169 e161-168. 
 
Butte M.J., Keir M.E., Phamduy T.B., Sharpe A.H. and Freeman G.J. "Programmed death-1 ligand 1 interacts 
specifically with the B7-1 costimulatory molecule to inhibit T cell responses." Immunity. (2007) 27(1): 
111-122. 
 
Cann C.I., Fried M.P. and Rothman K.J. "Epidemiology of squamous cell cancer of the head and neck." 
Otolaryngol Clin North Am. (1985) 18(3): 367-388. 
 
Carlos de Vicente J., Junquera Gutierrez L.M., Zapatero A.H., Fresno Forcelledo M.F., Hernandez-Vallejo G. and 
Lopez Arranz J.S. "Prognostic significance of p53 expression in oral squamous cell carcinoma without 
neck node metastases." Head Neck. (2004) 26(1): 22-30. 
 
Chaturvedi A.K. "Epidemiology and clinical aspects of HPV in head and neck cancers." Head Neck Pathol. (2012) 
6 Suppl 1: S16-24. 
 
Chaturvedi A.K., Engels E.A., Pfeiffer R.M., Hernandez B.Y., Xiao W., Kim E., Jiang B., Goodman M.T., Sibug-
Saber M., Cozen W., Liu L., Lynch C.F., Wentzensen N., Jordan R.C., Altekruse S., Anderson W.F., 
Rosenberg P.S. and Gillison M.L. "Human papillomavirus and rising oropharyngeal cancer incidence in 
the United States." Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. (2011) 29(32): 4294-4301. 
 
Chow L.Q., Haddad R., Gupta S., Mahipal A., Mehra R., Tahara M., Berger R., Eder J.P., Burtness B., Lee S.H., 
Keam B., Kang H., Muro K., Weiss J., Geva R., Lin C.C., Chung H.C., Meister A., Dolled-Filhart M., 
Pathiraja K., Cheng J.D. and Seiwert T.Y. "Antitumor Activity of Pembrolizumab in Biomarker-
Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results 
From the Phase Ib KEYNOTE-012 Expansion Cohort." J Clin Oncol. (2016). 
 
Christ M. "TG4001 - Local tolerance in the female rabbit by the intramuscular, subcutaneous and intradermal 
routes." Study Report (921/048) L'Arbresle, France, MDS Pharma Services, (2001) 
 
Chung C.H. and Gillison M.L. "Human papillomavirus in head and neck cancer: its role in pathogenesis and 
clinical implications." Clin Cancer Res. (2009) 15(22): 6758-6762. 
 
Chung H.C., Arkenau H.-T., Wyrwicz L., Oh D.Y., Lee K.-W., Infante J.R., Chin K.M., Von Heydebreck A., 
Kang Y.K. and Safran H. "Safety, PD-L1 expression, and clinical activity of avelumab (MSB0010718C), 
an anti-PD-L1 antibody, in patients with advanced gastric or gastroesophageal junction cancer." J Clin 
Oncol 34, 2016 (suppl 4S; abstr 167). (2016). 
 
Chung H.C., Ros W., Delord J.P., Perets R., Italiano A., Shapira-Frommer R., Manzuk L., Piha-Paul S.A., Xu L., 
Zeigenfuss S., Pruitt S.K. and Leary A. "Efficacy and Safety of Pembrolizumab in Previously Treated 
Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study." J Clin Oncol. (2019) 
37(17): 1470-1478. 

Transgene / Confidential 
Study Protocol TG4001.12 
Final Version 10.0 – 06 December 2023 
Page 125/160 
 
 
Cohen E.E.W., Soulieres D., Le Tourneau C., Dinis J., Licitra L., Ahn M.J., Soria A., Machiels J.P., Mach N., 
Mehra R., Burtness B., Zhang P., Cheng J., Swaby R.F., Harrington K.J. and investigators K.-. 
"Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck 
squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study." Lancet. (2019) 
393(10167): 156-167. 
 
Crook T., Tidy J.A. and Vousden K.H. "Degradation of p53 can be targeted by HPV E6 sequences distinct from 
those required for p53 binding and trans-activation." Cell. (1991) 67: 547-556. 
 
Curran M.A., Montalvo W., Yagita H. and Allison J.P. "PD-1 and CTLA-4 combination blockade expands 
infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors." Proc Natl 
Acad Sci U S A. (2010) 107(9): 4275-4280. 
 
D'Souza G., Kreimer A.R., Viscidi R., Pawlita M., Fakhry C., Koch W.M., Westra W.H. and Gillison M.L. "Case-
control study of human papillomavirus and oropharyngeal cancer." The New England journal of medicine. 
(2007) 356(19): 1944-1956. 
 
de Sanjose S., Quint W.G., Alemany L., Geraets D.T., Klaustermeier J.E., Lloveras B., Tous S., Felix A., Bravo 
L.E., Shin H.R., Vallejos C.S., de Ruiz P.A., Lima M.A., Guimera N., Clavero O., Alejo M., Llombart-
Bosch A., Cheng-Yang C., Tatti S.A., Kasamatsu E., Iljazovic E., Odida M., Prado R., Seoud M., Grce 
M., Usubutun A., Jain A., Suarez G.A., Lombardi L.E., Banjo A., Menendez C., Domingo E.J., Velasco 
J., Nessa A., Chichareon S.C., Qiao Y.L., Lerma E., Garland S.M., Sasagawa T., Ferrera A., Hammouda 
D., Mariani L., Pelayo A., Steiner I., Oliva E., Meijer C.J., Al-Jassar W.F., Cruz E., Wright T.C., Puras 
A., Llave C.L., Tzardi M., Agorastos T., Garcia-Barriola V., Clavel C., Ordi J., Andujar M., Castellsague 
X., Sanchez G.I., Nowakowski A.M., Bornstein J., Munoz N., Bosch F.X., Retrospective International S. 
and Group H.P.V.T.T.S. "Human papillomavirus genotype attribution in invasive cervical cancer: a 
retrospective cross-sectional worldwide study." Lancet Oncol. (2010) 11(11): 1048-1056. 
 
Dirix L.Y., Takacs I., Nikolinakos P., Jerusalem G., Arkenau H.T., Hamilton E.P.P., VonHeydebreck A., Grote 
H.J., Chin K. and Lippman M.E. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with 
locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. Thirty-Eighth 
Annual CTRC-AACR San Antonio Breast Cancer Symposium, San antonio, American Association for 
Cancer Research.(2015) 
 
Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R., Dancey J., Arbuck S., Gwyther S., 
Mooney M., Rubinstein L., Shankar L., Dodd L., Kaplan R., Lacombe D. and Verweij J. "New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)." European Journal of 
Cancer. (2009) 45(2): 228-247. 
 
Ferris R.L., Blumenschein G., Jr., Fayette J., Guigay J., Colevas A.D., Licitra L., Harrington K., Kasper S., Vokes 
E.E., Even C., Worden F., Saba N.F., Iglesias Docampo L.C., Haddad R., Rordorf T., Kiyota N., Tahara 
M., Monga M., Lynch M., Geese W.J., Kopit J., Shaw J.W. and Gillison M.L. "Nivolumab for Recurrent 
Squamous-Cell Carcinoma of the Head and Neck." N Engl J Med. (2016) 375(19): 1856-1867. 
 
Ferris R.L., Blumenschein G.R., Fayette J., Guigay J., Colevas A.D., Licitra L.F., Harrington K.J., Kasper S., 
Vokes E.E., Even C., Worden F.P., Haddad R.I., Kiyota N., Tahara M., Monga M., Lynch M.J., Geese 
W.J., Kopit J., Shaw J.W. and Gillison M.L. "Further evaluations of nivolumab (nivo) versus 
investigator’s choice (IC) chemotherapy for recurrent or metastatic (R/M) squamous cell carcinoma of 
the head and neck (SCCHN): CheckMate 141. ASCO Annual Meeting." J Clin Oncol 34, 2016 (suppl; 
abstr 6009). 
 
Fife B.T., Pauken K.E., Eagar T.N., Obu T., Wu J., Tang Q., Azuma M., Krummel M.F. and Bluestone J.A. 
"Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal." Nat 
Immunol. (2009) 10(11): 1185-1192. 
 
Freeman G.J., Long A.J., Iwai Y., Bourque K., Chernova T., Nishimura H., Fitz L.J., Malenkovich N., Okazaki 
T., Byrne M.C., Horton H.F., Fouser L., Carter L., Ling V., Bowman M.R., Carreno B.M., Collins M., 

Transgene / Confidential 
Study Protocol TG4001.12 
Final Version 10.0 – 06 December 2023 
Page 126/160 
 
Wood C.R. and Honjo T. "Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family 
member leads to negative regulation of lymphocyte activation." J Exp Med. (2000) 192(7): 1027-1034. 
 
Frenel J.S., Le Tourneau C., O'Neil B., Ott P.A., Piha-Paul S.A., Gomez-Roca C., van Brummelen E.M.J., Rugo 
H.S., Thomas S., Saraf S., Rangwala R. and Varga A. "Safety and Efficacy of Pembrolizumab in 
Advanced, Programmed Death Ligand 1-Positive Cervical Cancer: Results From the Phase Ib 
KEYNOTE-028 Trial." J Clin Oncol. (2017) 35(36): 4035-4041. 
 
Freshwater T., Kondic A., Ahamadi M., Li C.H., de Greef R., de Alwis D. and Stone J.A. "Evaluation of dosing 
strategy for pembrolizumab for oncology indications." J Immunother Cancer. (2017) 5: 43. 
 
Geng Y., Shao Y., He W., Hu W., Xu Y., Chen J., Wu C. and Jiang J. "Prognostic Role of Tumor-Infiltrating 
Lymphocytes in Lung Cancer: a Meta-Analysis." Cell Physiol Biochem. (2015) 37(4): 1560-1571. 
 
Gillison M.L., D'Souza G., Westra W., Sugar E., Xiao W., Begum S. and Viscidi R. "Distinct risk factor profiles 
for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck 
cancers." Journal of the National Cancer Institute. (2008) 100(6): 407-420. 
 
Gillison M.L., Koch W.M., Capone R.B., Spafford M., Westra W.H., Wu L., Zahurak M.L., Daniel R.W., Viglione 
M., Symer D.E., Shah K.V. and Sidransky D. "Evidence for a causal association between human 
papillomavirus and a subset of head and neck cancers." J Natl Cancer Inst. (2000a) 92(9): 709-720. 
 
Gillison M.L., Koch W.M., Capone R.B., Spafford M., Westra W.H., Wu L., Zahurak M.L., Daniel R.W., Viglione 
M., Symer D.E., Shah K.V. and Sidransky D. "Evidence for a causal association between human 
papillomavirus and a subset of head and neck cancers." Journal of the National Cancer Institute. (2000b) 
92(9): 709-720. 
 
Gillison M.L. and Shah K.V. "Human papillomavirus-associated head and neck squamous cell carcinoma: 
mounting evidence for an etiologic role for human papillomavirus in a subset of head and neck cancers." 
Curr Opin Oncol. (2001) 13(3): 183-188. 
 
GlaxoSmithKline Vaccine H.P.V.S.G., Romanowski B., de Borba P.C., Naud P.S., Roteli-Martins C.M., De 
Carvalho N.S., Teixeira J.C., Aoki F., Ramjattan B., Shier R.M., Somani R., Barbier S., Blatter M.M., 
Chambers C., Ferris D., Gall S.A., Guerra F.A., Harper D.M., Hedrick J.A., Henry D.C., Korn A.P., Kroll 
R., Moscicki A.B., Rosenfeld W.D., Sullivan B.J., Thoming C.S., Tyring S.K., Wheeler C.M., Dubin G., 
Schuind A., Zahaf T., Greenacre M. and Sgriobhadair A. "Sustained efficacy and immunogenicity of the 
human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-
controlled trial up to 6.4 years." Lancet. (2009) 374(9706): 1975-1985. 
 
Globocan. "Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012." (2012). 
 
Goldenberg D., Begum S., Westra W.H., Khan Z., Sciubba J., Pai S.I., Califano J.A., Tufano R.P. and Koch W.M. 
"Cystic lymph node metastasis in patients with head and neck cancer: An HPV-associated phenomenon." 
Head Neck. (2008) 30(7): 898-903. 
 
Gregoire V., Lefebvre J.L., Licitra L., Felip E. and Group E.-E.-E.G.W. "Squamous cell carcinoma of the head 
and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up." 
Ann Oncol. (2010) 21 Suppl 5: v184-186. 
 
Guigay J., Lee K.W., Patel M., Daste A., Wong D.J., Goel S., Gordon M., Gutierrez M., Balmanoukian A., Le 
Tourneau C., Mita A., D. Vansteene D., U. Keilholz U., Schöffski P., H. J. Grote H., D. Zhou D., Bajars 
M. and Penel N. Avelumab (anti–PD-L1) in patients with platinumrefractory/ineligible recurrent or 
metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): results from a phase 1b cohort. 
Abstract No. 4024. Presented at the ESMO Virtual Congress 2020.(19-21 September 2020). 
 
Haddad R.I. and Shin D.M. "Recent advances in head and neck cancer." N Engl J Med. (2008) 359(11): 1143-
1154. 
 

Transgene / Confidential 
Study Protocol TG4001.12 
Final Version 10.0 – 06 December 2023 
Page 127/160 
 
Halbert C., Demers G. and Galloway D. "The E7 gene of human papillomavirus type 16 is sufficient for 
immortalization of human epithelial cells." Journal of Virology. (1991) 65: 473-478. 
 
Hammarstedt L., Lindquist D., Dahlstrand H., Romanitan M., Dahlgren L.O., Joneberg J., Creson N., Lindholm 
J., Ye W., Dalianis T. and Munck-Wikland E. "Human papillomavirus as a risk factor for the increase in 
incidence of tonsillar cancer." Int J Cancer. (2006) 119(11): 2620-2623. 
 
Harper D.M., Franco E.L., Wheeler C.M., Moscicki A.B., Romanowski B., Roteli-Martins C.M., Jenkins D., 
Schuind A., Costa Clemens S.A., Dubin G. and group H.P.V.V.S. "Sustained efficacy up to 4.5 years of 
a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from 
a randomised control trial." Lancet. (2006) 367(9518): 1247-1255. 
 
Havre P.A., Yuan J., Hedrick L., Cho K.R. and Glazer P.M. "p53 inactivation by HPV16 E6 results in increased 
mutagenesis in human cells." Cancer Res. (1995) 55(19): 4420-4424. 
 
Herbst R.S., Soria J.C., Kowanetz M., Fine G.D., Hamid O., Gordon M.S., Sosman J.A., McDermott D.F., 
Powderly J.D., Gettinger S.N., Kohrt H.E., Horn L., Lawrence D.P., Rost S., Leabman M., Xiao Y., 
Mokatrin A., Koeppen H., Hegde P.S., Mellman I., Chen D.S. and Hodi F.S. "Predictive correlates of 
response to the anti-PD-L1 antibody MPDL3280A in cancer patients." Nature. (2014) 515(7528): 563-
567. 
 
Heusinkveld M., Goedemans R., Briet R.J., Gelderblom H., Nortier J.W., Gorter A., Smit V.T., Langeveld A.P., 
Jansen J.C. and van der Burg S.H. "Systemic and local human papillomavirus 16-specific T-cell immunity 
in patients with head and neck cancer." Int J Cancer. (2012) 131(2): E74-85. 
 
Hildesheim A., Schiffman M., Bromley C., Wacholder S., Herrero R., Rodriguez A., Bratti M.C., Sherman M.E., 
Scarpidis U., Lin Q.Q., Terai M., Bromley R.L., Buetow K., Apple R.J. and Burk R.D. "Human 
papillomavirus type 16 variants and risk of cervical cancer." J Natl Cancer Inst. (2001) 93(4): 315-318. 
 
Hollebecque A., Meyer T., Moore K.N., Machiels J.P.H., De Greve J., López-Picazo J.M., Oaknin A., Kerger J.N., 
Boni V., Evans T.R.J., Kristeleit R.S., Rao S., Soumaoro I., Cao Z.A. and L. T.S. "An open-label, 
multicohort, phase I/II study of nivolumab in patients with virus-associated tumors (CheckMate 358): 
Efficacy and safety in recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers." Journal of 
Clinical Oncology. (2017) 35(no. 15_suppl): 5504-5504. 
 
Howard S.C., Jones D.P. and Pui C.H. "The tumor lysis syndrome." N Engl J Med. (2011) 364(19): 1844-1854. 
 
Huang R.R., Jalil J., Economou J.S., Chmielowski B., Koya R.C., Mok S., Sazegar H., Seja E., Villanueva A., 
Gomez-Navarro J., Glaspy J.A., Cochran A.J. and Ribas A. "CTLA4 blockade induces frequent tumor 
infiltration by activated lymphocytes regardless of clinical responses in humans." Clin Cancer Res. (2011) 
17(12): 4101-4109. 
 
Ihloff A.S., Petersen C., Hoffmann M., Knecht R. and Tribius S. "Human papilloma virus in locally advanced 
stage III/IV squamous cell cancer of the oropharynx and impact on choice of therapy." Oral Oncol. (2010) 
46(10): 705-711. 
 
Ishida Y., Agata Y., Shibahara K. and Honjo T. "Induced expression of PD-1, a novel member of the 
immunoglobulin gene superfamily, upon programmed cell death." EMBO J. (1992) 11(11): 3887-3895. 
 
Iwai Y., Ishida M., Tanaka Y., Okazaki T., Honjo T. and Minato N. "Involvement of PD-L1 on tumor cells in the 
escape from host immune system and tumor immunotherapy by PD-L1 blockade." Proc Natl Acad Sci U 
S A. (2002) 99(19): 12293-12297. 
 
Kaiser S. "TG4001 – Subcutaneous toxicity study in C57 Black 6 mice after a repeated administration followed 
by a 4-week recovery period." Study Report (Study Report A85386.) RCC Ltd., Itigen and Füllinsdorf, 
Switzerland, (2007) 
 
Kaufman H.L., Russell J., Hamid O., Bhatia S., Terheyden P., D'Angelo S.P., Shih K.C., Lebbe C., Linette G.P., 
Milella M., Brownell I., Lewis K.D., Lorch J.H., Chin K., Mahnke L., von Heydebreck A., Cuillerot J.M. 

Transgene / Confidential 
Study Protocol TG4001.12 
Final Version 10.0 – 06 December 2023 
Page 128/160 
 
and Nghiem P. "Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a 
multicentre, single-group, open-label, phase 2 trial." Lancet Oncol. (2016) 17(10): 1374-1385. 
 
Keir M.E., Liang S.C., Guleria I., Latchman Y.E., Qipo A., Albacker L.A., Koulmanda M., Freeman G.J., Sayegh 
M.H. and Sharpe A.H. "Tissue expression of PD-L1 mediates peripheral T cell tolerance." J Exp Med. 
(2006) 203(4): 883-895. 
 
Kenter G.G., Welters M.J., Valentijn A.R., Lowik M.J., Berends-van der Meer D.M., Vloon A.P., Essahsah F., 
Fathers L.M., Offringa R., Drijfhout J.W., Wafelman A.R., Oostendorp J., Fleuren G.J., van der Burg 
S.H. and Melief C.J. "Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia." N 
Engl J Med. (2009) 361(19): 1838-1847. 
 
Khan M.M. "Immunosuppressive Agents. In: Immunopharmacology." New York: SpringerStudy Report  (2008) 
 
Kim S.H., Koo B.S. and Kang S. "HPV integration begins in the tonsillar crypt and leads to the alteration of p16, 
EGFR and c-myc during tumor formation." International Journal of Cancer. (2007) 7: 1418-1425. 
 
Klussmann J.P., Gultekin E., Weissenborn S.J., Wieland U., Dries V., Dienes H.P., Eckel H.E., Pfister H.J. and 
Fuchs P.G. "Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with 
human papillomavirus." Am J Pathol. (2003) 162(3): 747-753. 
 
Kreimer A.R., Clifford G.M., Boyle P. and Franceschi S. "Human papillomavirus types in head and neck squamous 
cell carcinomas worldwide: a systematic review." Cancer epidemiology, biomarkers & prevention : a 
publication of the American Association for Cancer Research, cosponsored by the American Society of 
Preventive Oncology. (2005) 14(2): 467-475. 
 
Kumar B., Cordell K.G., Lee J.S., Prince M.E., Tran H.H., Wolf G.T., Urba S.G., Worden F.P., Chepeha D.B., 
Teknos T.N., Eisbruch A., Tsien C.I., Taylor J.M., D'Silva N.J., Yang K., Kurnit D.M., Bradford C.R. 
and Carey T.E. "Response to therapy and outcomes in oropharyngeal cancer are associated with 
biomarkers including human papillomavirus, epidermal growth factor receptor, gender, and smoking." 
Int J Radiat Oncol Biol Phys. (2007) 69(2 Suppl): S109-111. 
 
Lassen P. "The role of Human papillomavirus in head and neck cancer and the impact on radiotherapy outcome." 
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 
(2010) 95(3): 371-380. 
 
Lassen P., Eriksen J.G., Hamilton-Dutoit S., Tramm T., Alsner J. and Overgaard J. "Effect of HPV-associated 
p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head 
and neck." Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 
(2009) 27(12): 1992-1998. 
 
Li Y., Hou S., Zhang X., Zhang G., Zhu J. and Wang X. "[Subpopulations of TIL in renal cell carcinoma and their 
clinical significance]." Zhonghua Wai Ke Za Zhi. (1998) 36(5): 314-316. 
 
Lindquist D., Romanitan M., Hammarstedt L., Nasman A., Dahlstrand H., Lindholm J., Onelov L., Ramqvist T., 
Ye W., Munck-Wikland E. and Dalianis T. "Human papillomavirus is a favourable prognostic factor in 
tonsillar cancer and its oncogenic role is supported by the expression of E6 and E7." Mol Oncol. (2007) 
1(3): 350-355. 
 
Lipponen P.K., Eskelinen M.J., Jauhiainen K., Harju E. and Terho R. "Tumour infiltrating lymphocytes as an 
independent prognostic factor in transitional cell bladder cancer." Eur J Cancer. (1992) 29A(1): 69-75. 
 
Liu J.Y., Li F., Wang L.P., Chen X.F., Wang D., Cao L., Ping Y., Zhao S., Li B., Thorne S.H., Zhang B., Kalinski 
P. and Zhang Y. "CTL- vs Treg lymphocyte-attracting chemokines, CCL4 and CCL20, are strong 
reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma." Br J 
Cancer. (2015) 113(5): 747-755. 
 
Lonardi S., Pietrantonio F., Prete A.A., Messina M., Renzi N., Corsi D.C., Urbano F., Frassineti G.L., Zampino 
M.G., Ronzoni M., Scartozzi M., Casagrande M., Boccaccino A., Bergamo F., Prisciandaro M., Rasola 

Transgene / Confidential 
Study Protocol TG4001.12 
Final Version 10.0 – 06 December 2023 
Page 129/160 
 
C., Corallo S., Del Bianco P., Vettore V. and Zagonel V. Randomized phase 2 trial of avelumab alone or 
with cetuximab for unresectable, locally advanced or metastatic squamous cell anal carcinoma 
progressed to at least one line of treatment: the CARACAS study. ASCO.(2020) 
 
Lyford-Pike S. and . e.a. PD-1:PD-L1(B7-H1) pathway in adaptive resistance: a novel mechanism for tumor 
immune escape in human papillomavirus-related head and neck cancers. ASCO Meet Abstr 2012; 30 
(15-suppl):550.(2012) 
 
Maby P., Tougeron D., Hamieh M., Mlecnik B., Kora H., Bindea G., Angell H.K., Fredriksen T., Elie N., 
Fauquembergue E., Drouet A., Leprince J., Benichou J., Mauillon J., Le Pessot F., Sesboue R., Tuech 
J.J., Sabourin J.C., Michel P., Frebourg T., Galon J. and Latouche J.B. "Correlation between Density of 
CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A 
Rationale for Personalized Immunotherapy." Cancer Res. (2015) 75(17): 3446-3455. 
 
Marabelle A., Cassier P., Fakih M., Kao S., Nielsen D., Italiano A., Guren T., Van Dongen M., Spencer K., Bariani 
G.M., Ascierto P., Santoro A., Hiret S., Ott P.A., Piha-Paul S.A., Liu C.C., Leiby M.A., Norwood K. and 
Delord J.P. Pembrolizumab for previously treated advanced anal squamous cell carcinoma: pooled 
results from the keynote-028 and keynote-158 studies. ASCO ANNUAL MEETING.(2020). 
 
Marur S., D'Souza G., Westra W.H. and Forastiere A.A. "HPV-associated head and neck cancer: a virus-related 
cancer epidemic." Lancet Oncol. (2010) 11(8): 781-789. 
 
Massarelli E., William W., Johnson F., Kies M., Ferrarotto R., Guo M., Feng L., Lee J.J., Tran H., Kim Y.U., 
Haymaker C., Bernatchez C., Curran M., Zecchini Barrese T., Rodriguez Canales J., Wistuba I., Li L., 
Wang J., van der Burg S.H., Melief C.J. and Glisson B. "Combining Immune Checkpoint Blockade and 
Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16-Related Cancer: A Phase 
2 Clinical Trial." JAMA Oncol. (2019) 5(1): 67-73. 
 
Mehanna H., Beech T., Nicholson T., El-Hariry I., McConkey C., Paleri V. and Roberts S. "Prevalence of human 
papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer--systematic review and 
meta-analysis of trends by time and region." Head Neck. (2013) 35(5): 747-755. 
 
Mehta C.R. and Pocock S.J. "Adaptive increase in sample size when interim results are promising: a practical 
guide with examples." Stat Med. (2011) 30(28): 3267-3284. 
 
Melero I., Berman D.M., Aznar M.A., Korman A.J., Perez Gracia J.L. and Haanen J. "Evolving synergistic 
combinations of targeted immunotherapies to combat cancer." Nature reviews. Cancer. (2015) 15(8): 
457-472. 
 
Mellin Dahlstrand H., Lindquist D., Bjornestal L., Ohlsson A., Dalianis T., Munck-Wikland E. and Elmberger G. 
"P16(INK4a) correlates to human papillomavirus presence, response to radiotherapy and clinical outcome 
in tonsillar carcinoma." Anticancer Res. (2005) 25(6C): 4375-4383. 
 
Menguy T. "In vitro assessment of the transformation potential of mammalian cells by human papilloma virus 16 
(HPV16) E6 and E7 sequences used in RO5217790." Study Report (DP0400) Strasbourg, Transgene, 
(2009) 
 
Morris V.K., Salem M.E., Nimeiri H., Iqbal S., Singh P., Ciombor K., Polite B., Deming D., Chan E., Wade J.L., 
Xiao L., Bekaii-Saab T., Vence L., Blando J., Mahvash A., Foo W.C., Ohaji C., Pasia M., Bland G., 
Ohinata A., Rogers J., Mehdizadeh A., Banks K., Lanman R., Wolff R.A., Streicher H., Allison J., Sharma 
P. and Eng C. "Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a 
multicentre, single-arm, phase 2 study." Lancet Oncol. (2017) 18(4): 446-453. 
 
Munger K., Werness B.A., Dyson N., Phelps W.C., Harlow E. and Howley P.M. "Complex formation of human 
papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product." The EMBO journal. 
(1989) 8(13): 4099-4105. 
 

Transgene / Confidential 
Study Protocol TG4001.12 
Final Version 10.0 – 06 December 2023 
Page 130/160 
 
Nashina T, Shitara K, Iwasa S and al e. "Safety, PD-L1 expression, and clinical activity of avelumab 
(MSB0010718C), an anti-PD-L1 antibody, in Japanese patients with advanced gastric or 
gastroesophageal junction cancer." J Clin Oncol 34 (suppl 4S; abstr 168). (2016 ). 
 
Nasman A., Attner P., Hammarstedt L., Du J., Eriksson M., Giraud G., Ahrlund-Richter S., Marklund L., 
Romanitan M., Lindquist D., Ramqvist T., Lindholm J., Sparen P., Ye W., Dahlstrand H., Munck-
Wikland E. and Dalianis T. "Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in 
Stockholm, Sweden: an epidemic of viral-induced carcinoma?" Int J Cancer. (2009) 125(2): 362-366. 
 
Nevins J.R. "The Rb/E2F pathway and cancer." Hum Mol Genet. (2001) 10(7): 699-703. 
 
Ott P.A., Piha-Paul S.A., Munster P., Pishvaian M.J., van Brummelen E.M.J., Cohen R.B., Gomez-Roca C., Ejadi 
S., Stein M., Chan E., Simonelli M., Morosky A., Saraf S., Emancipator K., Koshiji M. and Bennouna J. 
"Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent 
carcinoma of the anal canal." Ann Oncol. (2017) 28(5): 1036-1041. 
 
Palefsky J.M. and Holly E.A. "Molecular virology and epidemiology of human papillomavirus and cervical 
cancer." Cancer Epidemiol Biomarkers Prev. (1995) 4(4): 415-428. 
 
Paul S. "Evaluation of the adjuvant effect of topical administration of Aldara on the therapeutic efficacy of 
MVATG8042." Study Report (DP0339) Transgene, Strasbourg, (2007) 
 
Pecheur C. "TG4001 - Four week intramuscular toxicity study in the rat (2 administrations per week)." Study 
Report (921/025) Chrysalis S.A., L'Arbresle, France, (1998a) 
 
Pecheur C. "TG4001 - Single dose intravenous (bolus) toxicity study in the rat followed by a 14-day observation 
period." Study Report (921/026) Chrysalis S.A., L'Arbresle, France, (1998b) 
 
Pecheur C. and Bizouarne N. "Mechanisms of tumour rejection : Effect of CD4 or CD8 depletion before 
immunization with MVATG8042 -Immunoprophylaxis experiment in a mouse model of cervical cancer." 
Study Report (DP0068) Transgene, Strasbourg, (2000) 
 
Peng S., Best S.R., Hung C.F., Loyo M., Lyford-Pike S., Flint P.W., Tunkel D.E., Saunders J.R., Wu T.C. and Pai 
S.I. "Characterization of human papillomavirus type 11-specific immune responses in a preclinical 
model." Laryngoscope. (2010) 120(3): 504-510. 
 
Rotnaglova E., Tachezy R., Salakova M., Prochazka B., Kosl'abova E., Vesela E., Ludvikova V., Hamsikova E. 
and Klozar J. "HPV involvement in tonsillar cancer: prognostic significance and clinically relevant 
markers." Int J Cancer. (2011) 129(1): 101-110. 
 
Schleimer R.P., Jacques A., Shin H.S., Lichtenstein L.M. and Plaut M. "Inhibition of T cell-mediated cytotoxicity 
by anti-inflammatory steroids." J Immunol. (1984) 132(1): 266-271. 
 
Schlom J. "Therapeutic cancer vaccines: current status and moving forward." J Natl Cancer Inst. (2012) 104(8): 
599-613. 
 
Seiwert T.Y., Burtness B., Mehra R., Weiss J., Berger R., Eder J.P., Heath K., McClanahan T., Lunceford J., Gause 
C., Cheng J.D. and Chow L.Q. "Safety and clinical activity of pembrolizumab for treatment of recurrent 
or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, 
multicentre, phase 1b trial." Lancet Oncol. (2016) 17(7): 956-965. 
 
Sharma P., Shen Y., Wen S., Yamada S., Jungbluth A.A., Gnjatic S., Bajorin D.F., Reuter V.E., Herr H., Old L.J. 
and Sato E. "CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial 
carcinoma." Proc Natl Acad Sci U S A. (2007) 104(10): 3967-3972. 
 
Shiboski C.H., Schmidt B.L. and Jordan R.C. "Tongue and tonsil carcinoma: increasing trends in the U.S. 
population ages 20-44 years." Cancer. (2005) 103(9): 1843-1849. 
 

Transgene / Confidential 
Study Protocol TG4001.12 
Final Version 10.0 – 06 December 2023 
Page 131/160 
 
Siegel R., Naishadham D. and Jemal A. "Cancer statistics, 2012." CA Cancer J Clin. (2012) 62(1): 10-29. 
 
Smeets S.J., Braakhuis B.J., Abbas S., Snijders P.J., Ylstra B., van de Wiel M.A., Meijer G.A., Leemans C.R. and 
Brakenhoff R.H. "Genome-wide DNA copy number alterations in head and neck squamous cell 
carcinomas with or without oncogene-expressing human papillomavirus." Oncogene. (2006) 25(17): 
2558-2564. 
 
Smith E.M., Ritchie J.M., Summersgill K.F., Klussmann J.P., Lee J.H., Wang D., Haugen T.H. and Turek L.P. 
"Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers." 
International journal of cancer. Journal international du cancer. (2004) 108(5): 766-772. 
 
Spanos W.C., Nowicki P., Lee D.W., Hoover A., Hostager B., Gupta A., Anderson M.E. and Lee J.H. "Immune 
response during therapy with cisplatin or radiation for human papillomavirus-related head and neck 
cancer." Arch Otolaryngol Head Neck Surg. (2009) 135(11): 1137-1146. 
 
Sturgis E.M. and Ang K.K. "The epidemic of HPV-associated oropharyngeal cancer is here: is it time to change 
our treatment paradigms?" J Natl Compr Canc Netw. (2011) 9(6): 665-673. 
 
Tilston P. "Anal human papillomavirus and anal cancer." J Clin Pathol. (1997) 50(8): 625-634. 
 
Topalian S.L., Hodi F.S., Brahmer J.R., Gettinger S.N., Smith D.C., McDermott D.F., Powderly J.D., Carvajal 
R.D., Sosman J.A., Atkins M.B., Leming P.D., Spigel D.R., Antonia S.J., Horn L., Drake C.G., Pardoll 
D.M., Chen L., Sharfman W.H., Anders R.A., Taube J.M., McMiller T.L., Xu H., Korman A.J., Jure-
Kunkel M., Agrawal S., McDonald D., Kollia G.D., Gupta A., Wigginton J.M. and Sznol M. "Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer." The New England journal of medicine. 
(2012) 366(26): 2443-2454. 
 
Tsujihashi H., Matsuda H., Uejima S., Akiyama T. and Kurita T. "Immunocompetence of tissue infiltrating 
lymphocytes in bladder tumors." J Urol. (1988) 140(4): 890-894. 
 
Tumeh P.C., Hellmann M.D., Hamid O., Tsai K.K., Loo K.L., Gubens M.A., Rosenblum M., Harview C.L., Taube 
J.M., Handley N., Khurana N., Nosrati A., Krummel M.F., Tucker A., Sosa E.V., Sanchez P.J., Banayan 
N., Osorio J.C., Nguyen-Kim D.L., Chang J., Shintaku I.P., Boasberg P.D., Taylor E.J., Munster P.N., 
Algazi A.P., Chmielowski B., Dummer R., Grogan T.R., Elashoff D., Hwang J., Goldinger S.M., Garon 
E.B., Pierce R.H. and Daud A. "Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal 
Antibody in Patients with Melanoma and NSCLC." Cancer Immunol Res. (2017) 5(5): 417-424. 
 
Varma V.A., Sanchez-Lanier M., Unger E.R., Clark C., Tickman R., Hewan-Lowe K., Chenggis M.L. and Swan 
D.C. "Association of human papillomavirus with penile carcinoma: a study using polymerase chain 
reaction and in situ hybridization." Hum Pathol. (1991) 22(9): 908-913. 
 
Villa L.L., Ault K.A., Giuliano A.R., Costa R.L., Petta C.A., Andrade R.P., Brown D.R., Ferenczy A., Harper 
D.M., Koutsky L.A., Kurman R.J., Lehtinen M., Malm C., Olsson S.E., Ronnett B.M., Skjeldestad F.E., 
Steinwall M., Stoler M.H., Wheeler C.M., Taddeo F.J., Yu J., Lupinacci L., Railkar R., Marchese R., 
Esser M.T., Bryan J., Jansen K.U., Sings H.L., Tamms G.M., Saah A.J. and Barr E. "Immunologic 
responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 
18." Vaccine. (2006) 24(27-28): 5571-5583. 
 
Voskens C.J., Sewell D., Hertzano R., DeSanto J., Rollins S., Lee M., Taylor R., Wolf J., Suntharalingam M., 
Gastman B., Papadimitriou J.C., Lu C., Tan M., Morales R., Cullen K., Celis E., Mann D. and Strome 
S.E. "Induction of MAGE-A3 and HPV-16 immunity by Trojan vaccines in patients with head and neck 
carcinoma." Head Neck. (2012) 34(12): 1734-1746. 
 
Wang D.D., Zhang S., Zhao H., Men A.Y. and Parivar K. "Fixed dosing versus body size-based dosing of 
monoclonal antibodies in adult clinical trials." J Clin Pharmacol. (2009) 49(9): 1012-1024. 
 
Weber J.S., Kahler K.C. and Hauschild A. "Management of immune-related adverse events and kinetics of 
response with ipilimumab." J Clin Oncol. (2012) 30(21): 2691-2697. 
 

Transgene / Confidential 
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Weinberger P.M., Yu Z., Haffty B.G., Kowalski D., Harigopal M., Brandsma J., Sasaki C., Joe J., Camp R.L., 
Rimm D.L. and Psyrri A. "Molecular classification identifies a subset of human papillomavirus--
associated oropharyngeal cancers with favorable prognosis." Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. (2006) 24(5): 736-747. 
 
Whiteside T.L. "Anti-tumor vaccines in head and neck cancer: targeting immune responses to the tumor." Curr 
Cancer Drug Targets. (2007) 7(7): 633-642. 
 
Wilczynski S.P., Lin B.T., Xie Y. and Paz I.B. "Detection of human papillomavirus DNA and oncoprotein 
overexpression are associated with distinct morphological patterns of tonsillar squamous cell carcinoma." 
Am J Pathol. (1998) 152(1): 145-156. 
 
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. 
 
Zhao X., Suryawanshi S., Hruska M., Feng Y., Wang X., Shen J., Vezina H.E., McHenry M.B., Waxman I.M., 
Achanta A., Bello A., Roy A. and Agrawal S. "Assessment of nivolumab benefit-risk profile of a 240-mg 
flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors." Ann Oncol. (2017) 
28(8): 2002-2008. 
 
 

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APPENDICES 
 
APPENDIX I  
PERFORMANCE STATUS (ECOG) SCALE 
APPENDIX II 
CONTRACEPTIVE 
GUIDANCE 
AND 
WOMAN 
OF 
CHILDBEARING POTENTIAL 
APPENDIX IIIA  
STUDY FLOW-CHART Phase Ib and phase II part 1  
[Baseline to Month 6 Day 204] 
APPENDIX IIIB  
STUDY FLOW-CHART Phase Ib and phase II part 1 
From [Day 204 to end of study]  
APPENDIX IIIC  
STUDY FLOW-CHART Phase II part 2  
[Baseline to Month 6 Day 204] 
APPENDIX IIID  
STUDY FLOW-CHART Phase II part 2 
From [Day 204 to end of study]  
APPENDIX IV  
ASSESSMENT 
OF 
EFFICACY 
ACCORDING 
TO 
RECIST 
APPENDIX V 
AVELUMAB SUMMARY OF SAFETY PROFILE 
 
 
 
 
 
 
 
 
 

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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 all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
 
3. Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. 
 
4. Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
 
 
 

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APPENDIX II: Contraceptive Guidance and Woman of Childbearing 
Potential 
Birth control methods considered as highly effective 
According to the Clinical Trials Facilitation Group (CTFG) “Recommendations related to 
contraception and pregnancy testing in clinical trials” methods that can achieve a failure rate of 
less than 1% per year when used consistently and correctly are considered as highly effective 
birth control methods, such as: 
- 
combined (estrogen and progesterone containing) hormonal contraception associated 
with inhibition of ovulation1 (oral, intravaginal, transdermal) 
- 
progesterone-only hormonal contraception associated with inhibition of ovulation1 
(oral, injectable, implantable2) 
- 
intrauterine device (IUD)2 
- 
intrauterine hormone-releasing system (IUS)2 
- 
bilateral tubal occlusion2 
- 
vasectomized partner2,3 
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method 
2 Contraception methods in the context of this guidance are considered to have low user dependency 
3 Vasectomised partner is a highly effective birth control method provided that the partner is the sole sexual partner 
of the woman of childbearing potential trial participant and that the vasectomized partner has received medical 
assessment of the surgical success. If not, an additional highly effective method of contraception should be used.   
 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
 
Women in the following categories are not considered WOCBP 
1. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: review of participant’s medical 
records, medical examination, or medical history interview. 
2. Premenarchal  
3. Postmenopausal female 
- 
Postmenopausal state is defined as ≥ 12 months of non-therapy-induced amenorrhea 
(A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a post-menopausal state in women not using hormonal 

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contraception or hormonal replacement therapy). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.  
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Postmenopausal female or who have undergone hysterectomy or bilateral oophorectomy are 
exempt from pregnancy testing. 
 
Contraceptive Guidance 
 
Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of 
ovulationb  
oral  
intravaginal  
transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulationb  
oral  
injectable  
Highly Effective Methods That Are User Independent  
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method. In this case two highly effective methods of contraception should be utilized during 
the treatment period and for at least 3 months after the last dose of study treatment  
 
 
 
 

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APPENDIX IIIA: Phase Ib and phase II part 1 Study Flow-Chart [Baseline to Month 6 Day 204] 
 
Baseline 
Study treatment period from [Baseline to Month 6 Day 204]  
Day 
Day 
Day 
Day 
Day 
Day 
Study days* 
-21/ 
0 
-7/ 
0 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 120 127 
134 
141 148 155 162 169 176 
183 
190 197 204 
Injection TG4001a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Avelumab administrationb 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Demography, history of 
studied disease, HPV status, 
relevant medical history / 
current medical conditions 
and signs and symptomsc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
check 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluation and body 
weighte 
Xd 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Performance statuse 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Cardiac evaluation (12-lead 
ECG)f 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events reporting 
Xg 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Concomitant medications and 
significant non-drug therapies 
collection 
Xh 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Tumor evaluationi 
X 
 
 
 
 
 
 
 
Xj 
 
 
 
 
 
Xj 
 
 
 
 
 
Xj 
 
 
 
 
 
Xj 
 
 
 
 
 
Further antineoplastic 
therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologye,k 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Biochemistry, creatininee,k 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Free T4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSHe,k 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
HIV and HCV serology; 
detection of antigen HBs 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testl,e,k 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
HLA typinge 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Baseline 
Study treatment period from [Baseline to Month 6 Day 204]  
Day 
Day 
Day 
Day 
Day 
Day 
Study days* 
-21/ 
0 
-7/ 
0 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 120 127 
134 
141 148 155 162 169 176 
183 
190 197 204 
Tumor samples (repeated 
biopsy) 
Xm 
 
 
 
 
 
 
 
Xm 
 
 
 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunological testse 
 
Xq 
Xo 
Xp 
 
 
 
 
Xq 
 
 
 
 
 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xq 
* The time windows allowed for the visits are: +/- 1 day from Day 1 to Day 36; - 3 / + 1 days for the further study treatments visits beyond Day 36 
a TG4001 will be administered SC on a weekly basis on Days 1, 8, 15, 22 and 29 then once every 2 weeks (starting from Day 36) up to Month 6, thereafter every 12 weeks until disease progression, 
unacceptabe toxicity, patient withdrawal from study for any reason or for a maximum of 2 years, whichever occurs first.** 
b Avelumab will be administered as an IV infusion once every 2 weeks starting on Day 8 (one week after the first dose of TG4001) until disease progression, unacceptabe toxicity, patient 
withdrawal from study for any reason or for a maximum of 2 years, whichever occurs first.** The bi-weekly 14-day schedule should be strictly adhered to, and patients should return to the target 
date (i.e. the next regularly scheduled visit relative to the start of avelumab) even if the previous visit was off schedule.  
c From the date of signature of the ICF and before first study treatment administration for medical history, current medical conditions, signs and symptoms  
d Height will be collected only at baseline.  
e If during visits with study treatment administration, to be performed prior to study treatment administration. 
f Repeated during study treatment as clinically indicated (see Section 7.3). 
g From start of study treatment except for SAE which must be collected from signature date of ICF 
h Since 1 month prior to study treatment start. 
i Includes the following: preferably CT (or MRI) of the head and neck, chest, abdomen and all other known sites of disease (e.g. pelvis, if applicable); and an adequate radiological and/or isotopical 
exploration in case of bone pain. Tumor evaluation will be assessed locally using RECIST 1.1 at baseline and during the study. The same technique (CT/MRI) used at baseline should be utilized 
throughout the study. 
j Tumor evaluation must be performed every 6 weeks for the first 9 months from treatment start and every 12 weeks thereafter, with a time window allowed of +/- 7 days . 
k During the study, hematology and serum chemistry (and pregnancy test, if applicable) will be evaluated by local laboratories. The results of hematology and chemistry (and pregnancy test, if 
applicable) must be reviewed before study treatment administration. Local labs may be drawn up to 2 days before study treatment administration to meet this requirement.  
l For women of childbearing potential 
m Tumor biopsy; mandatory at baseline and on Day 43. 
n Tumor biopsy on Day 85 unless it is unsafe or undesirable. 
o One blood collection of 29 ml. 
p Does not include blood collection for  PBMC, blood collection is limited to 11.5 ml. 
q One blood collection of 49 ml. 
 

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APPENDIX IIIB: Phase Ib and phase II part 1 STUDY FLOW-CHART From [Day 204 to end of study] 
  
 
Study treatment Period from 
[Day 204 to end of treatment] 
End of 
treatment 
visitr 
Safety follow-up visits 
PFS-FU 
visitj 
OS-
FUu 
Study days* 
Every 2 
Weeks 
Every 6 
weeks 
Every 12 
weeks 
Month 
12  
Month 
24  
 
 30 days 
after last 
study 
treatments 
90 days after 
last dose 
(phone call)t 
 
 
Injection TG4001a 
 
 
 
 
 
 
 
 
 
 
Avelumab administrationb 
X 
 
 
 
 
 
 
 
 
 
Clinical evaluation and body weighte 
X 
 
 
 
 
X 
X 
 
 
 
Performance statuse 
X 
 
 
 
 
X 
 
 
 
 
Cardiac evaluation (12-lead ECG)f 
 
 
 
 
 
X 
 
 
 
 
Adverse events reporting 
X 
 
 
 
 
X 
X 
X 
 
 
Concomitant medications and significant 
non-drug therapies collection 
X 
 
 
 
 
X 
X 
 
 
 
Tumor evaluation i 
 
Xj 
Xj 
 
 
 
 
 
X 
 
Further antineoplastic therapies 
 
 
 
 
 
X 
X 
X 
X 
X 
Hematologye,k 
 
X 
 
 
 
X 
X 
 
 
 
Biochemistry, creatininee,k 
 
X 
 
 
 
X 
X 
 
 
 
Pregnancy testl,e,k 
 
X 
 
 
 
X 
X 
 
 
 
Free T4 
 
 
 
 
 
X 
 
 
 
 
TSHe,k 
 
X 
 
 
 
X 
 
 
 
 
Immunological testse 
 
 
 
Xq 
Xq 
 
 
 
 
 
 
* The time windows allowed for these visits is - 3 / + 1 days 
a TG4001 will be administered SC every 12 weeks until disease progression, unacceptabe toxicity, patient withdrawal from study for any reason or for a maximum of 2 years, whichever occurs 
first.**  
b Avelumab will be administered as an IV infusion once every 2 weeks until disease progression, unacceptabe toxicity, patient withdrawal from study for any reason or for a maximum of 2 years, 
whichever occurs first.** The bi-weekly 14-day schedule should be strictly adhered to, and patients should return to the target date (i.e. the next regularly scheduled visit relative to the start of 
avelumab) even if the previous visit was off schedule.   
e If during visits with study treatment administration, to be performed prior to study treatment administration. 

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f Repeated during study treatment as clinically indicated (see Section 7.3). 
i Includes the following: preferably CT (or MRI) of the head and neck, chest, abdomen and all other known sites of disease (e.g. pelvis, if applicable); and an adequate radiological and/or isotopical 
exploration in case of bone pain . Tumor evaluation will be assessed locally using RECIST 1.1 at baseline and during the study. The same technique (CT/MRI) used at baseline should be utilized 
throughout the study. 
j Tumor evaluation must be performed every 6 weeks for the first 9 months from treatment start and every 12 weeks thereafter, with a time window allowed of +/- 7 days . 
k During the study, hematology and serum chemistry (and pregnancy test, if applicable) will be evaluated by local laboratories. The results of hematology and chemistry (and pregnancy test, if 
applicable) must be reviewed before study treatment administration. Local labs may be drawn up to 2 days before study treatment administration to meet this requirement. 
l For women of childbearing potential 
q One blood collection of 49 ml. 
r For each patient, an end of treatment visit (EOT) will be scheduled once the patient is discontinued from all study treatments. 
s Must occur 30 days after the last study treatment administration. All AEs and SAEs will be documented until this visit. 
t Must occur 90 days after the last study treatment administration. Patients will be contacted by telephone to collect information on new or ongoing SAEs and treatment-related non-serious AEs. 
Any SAE assessed as related to IMPs must be reported whenever it occurs, irrespective of the time elapsed since the last administration of IMPs. Patients with an ongoing SAE at the 90-day Safety 
Follow-up Phone Call must be monitored and followed by the Investigator until stabilization or until the outcome is known, unless the subject is documented as “lost to follow-up”. 
u Long-term follow-up for survival, every 3 months after the safety follow-up visit or last PFS follow-up visit (may be performed by phone contact). 
 
** Beyond 2 years of treatment and based on the clinical judgement of the investigator the patient could continue to receive study treatments. 
 
 

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APPENDIX IIIC: Phase II part 2 Study Flow-Chart [Baseline to Month 6 Day 204] 
 
Baseline 
Study treatment period from [Baseline to Month 6 Day 204] 
 
 
Day 
Day 
Day 
Day 
Day 
Day 
Study days* 
-21/ 
0 
-3/ 
0 
1 
1 
+ 6h 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 106 113 120 127 134 141 148 155 162 169 176 183 190 197 204 
In the combination arm 
Injection TG4001a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In both arms 
Avelumab 
administrationb 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, history 
of studied disease, 
HPV status, relevant 
medical history / 
current medical 
conditions and signs 
and symptomsc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria check 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluation and 
body weighte 
Xd 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Pulse oximetry on 
room air 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance statuse 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Cardiac evaluation (12-
lead ECG)f 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
reporting 
Xg 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Concomitant 
medications and 
significant non-drug 
therapies collection 
Xh 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Tumor evaluationi 
X 
 
 
 
 
 
 
 
 
Xj 
 
 
 
 
 
Xj 
 
 
 
 
 
Xj 
 
 
 
 
 
Xj 
 
 
 
 
 
Further antineoplastic 
therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologye,k 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Biochemistry, 
creatininee,k 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 

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Baseline 
Study treatment period from [Baseline to Month 6 Day 204] 
 
 
Day 
Day 
Day 
Day 
Day 
Day 
Study days* 
-21/ 
0 
-3/ 
0 
1 
1 
+ 6h 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 106 113 120 127 134 141 148 155 162 169 176 183 190 197 204 
Free T4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSHe,k 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
HIV and HCV serology; 
detection of antigen 
HBs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testl,e,k 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Tumor samples 
(repeated biopsy) 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunological testse 
 
Xq 
Xo 
Xr 
Xp 
Xq 
 
 
 
Xq 
 
 
 
 
 
Xq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xq 
* The time windows allowed for the visits are: +/- 1 day from Day 1 to Day 36; - 3 / + 1 days for the further study treatments visits beyond Day 36 
a TG4001 will be administered SC on a weekly basis on Days 1, 8, 15, 22 and 29 then once every 2 weeks (starting from Day 36) up to Month 6 (Day 204) , thereafter every 12 weeks until disease progression, unacceptable toxicity, patient withdrawal 
from study for any reason or for a maximum of 2 years, whichever occurs first.** 
b Avelumab will be administered as an IV infusion once every 2 weeks starting on Day 8 until disease progression, unacceptable toxicity, patient withdrawal from study for any reason or for a maximum of 2 years, whichever occurs first.** The bi-
weekly 14-day schedule should be strictly adhered to, and patients should return to the target date (i.e. the next regularly scheduled visit relative to the start of avelumab) even if the previous visit was off schedule.  
c From the date of signature of the ICF and before first study treatment administration for medical history, current medical conditions, signs and symptoms  
d Height will be collected only at baseline.  
e If during visits with study treatment administration, to be performed prior to study treatment administration. 
f Repeated during study treatment as clinically indicated (see Section 7.3). 
g From start of study treatment except for SAE which must be collected from signature date of ICF 
h Since 1 month prior to study treatment start. 
i Includes the following: preferably CT (or MRI) of the head and neck, chest, abdomen and all other known sites of disease (e.g. pelvis, if applicable); and an adequate radiological and/or isotopical exploration in case of bone pain. Tumor evaluation 
will be assessed locally using RECIST 1.1 at baseline and during the study. The same technique (CT/MRI) used at baseline should be utilized throughout the study. 
j Tumor evaluation must be performed every 6 weeks for the first 9 months from treatment start and every 12 weeks thereafter, with a time window allowed of +/- 7 days . 
k During the study, hematology and serum chemistry (and pregnancy test, if applicable) will be evaluated by local laboratories. The results of hematology and chemistry (and pregnancy test, if applicable) must be reviewed before study treatment 
administration. Local labs may be drawn up to 2 days before study treatment administration to meet this requirement.  
l For women of childbearing potential 
m Tumor biopsy; mandatory at baseline and on Day 85 for patients with accessible lesions. For patients without accessible lesions at baseline, archived tumor tissue must be available at baseline for determination of HPV-16 positivity and an archival 
sample obtained within one year prior to randomization must be available for translational analysis. 
o Blood collection of 24 ml. 
p Does not include blood collection for PBMC, blood collection is limited to 9 ml. 

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q Blood collection of 59 ml. 
r One blood collection of 9 ml. Only for patients in combination arm treated with TG4001. Time window allowed is +/- 30min. 
 
APPENDIX IIID: Phase II part 2 STUDY FLOW-CHART From [Day 204 to end of study] 
 
 
Study treatment Period from  
[Day 204 to end of treatment] 
End of 
treatment 
visitr 
Safety follow-up visits 
PFS-FU 
visitj 
OS-
FUu 
Study days* 
Every 2 
Weeks 
Every 6 
weeks 
Every 
12 
weeks 
Month 
9 Day 
288 
Month 
12 Day 
372 
 
 30 days 
after last 
study 
treatments 
90 days 
after last 
dose 
(phone call)t 
 
 
In the combination arm 
Injection TG4001a 
 
 
 
 
 
 
 
 
 
 
In both arms 
Avelumab administrationb 
X 
 
 
 
 
 
 
 
 
 
Clinical evaluation and body weighte 
X 
 
 
 
 
X 
X 
 
 
 
Performance statuse 
X 
 
 
 
 
X 
 
 
 
 
Cardiac evaluation (12-lead ECG)f 
 
 
 
 
 
X 
 
 
 
 
Adverse events reporting 
X 
 
 
 
 
X 
X 
X 
 
 
Concomitant 
medications 
and 
significant 
non-drug 
therapies 
collection 
X 
 
 
 
 
X 
X 
 
 
 
Tumor evaluation i 
 
Xj 
Xj 
 
 
 
 
 
X 
 
Further antineoplastic therapies 
 
 
 
 
 
X 
X 
X 
X 
X 
Hematologye,k 
 
X 
 
 
 
X 
X 
 
 
 
Biochemistry, creatininee,k 
 
X 
 
 
 
X 
X 
 
 
 
Pregnancy testl,e,k 
 
X 
 
 
 
X 
X 
 
 
 
Free T4 
 
 
 
 
 
X 
 
 
 
 
TSHe,k 
 
X 
 
 
 
X 
 
 
 
 
Tumor samples (repeated biopsy) 
 
 
 
X 
 
Xv 
 
 
Xv 
 
Immunological testse 
 
 
 
Xq 
Xp 
 
 
 
 
 
 
* The time windows allowed for these visits is - 3 / + 1 days 

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a TG4001 will be administered SC every 12 weeks until disease progression, unacceptable toxicity, patient withdrawal from study for any reason or for a maximum of 2 years, whichever occurs 
first.**  
b Avelumab will be administered as an IV infusion once every 2 weeks until disease progression, unacceptable toxicity, patient withdrawal from study for any reason or for a maximum of 2 years, 
whichever occurs first.** The bi-weekly 14-day schedule should be strictly adhered to, and patients should return to the target date (i.e. the next regularly scheduled visit relative to the start of 
avelumab) even if the previous visit was off schedule.   
e If during visits with study treatment administration, to be performed prior to study treatment administration. 
f Repeated during study treatment as clinically indicated (see Section 7.3). 
i Includes the following: preferably CT (or MRI) of the head and neck, chest, abdomen and all other known sites of disease (e.g. pelvis, if applicable); and an adequate radiological and/or isotopical 
exploration in case of bone pain. Tumor evaluation will be assessed locally using RECIST 1.1 at baseline and during the study. The same technique (CT/MRI) used at baseline should be utilized 
throughout the study. 
j Tumor evaluation must be performed every 6 weeks for the first 9 months from treatment start and every 12 weeks thereafter, with a time window allowed of +/- 7 days. 
k During the study, hematology and serum chemistry (and pregnancy test, if applicable) will be evaluated by local laboratories. The results of hematology and chemistry (and pregnancy test, if 
applicable) must be reviewed before study treatment administration. Local labs may be drawn up to 2 days before study treatment administration to meet this requirement. 
l For women of childbearing potential 
p Does not include blood collection for PBMC, blood collection is limited to 9 ml. 
q Blood collection of 59 ml. 
r For each patient, an end of treatment visit (EOT) will be scheduled once the patient is discontinued from all study treatments. 
s Must occur 30 days after the last study treatment administration. All AEs and SAEs will be documented until this visit. 
t Must occur 90 days after the last study treatment administration. Patients will be contacted by telephone to collect information on new or ongoing SAEs and treatment-related non-serious AEs. 
Any SAE assessed as related to IMPs must be reported whenever it occurs, irrespective of the time elapsed since the last administration of IMPs. Patients with an ongoing SAE at the 90-day Safety 
Follow-up Phone Call must be monitored and followed by the Investigator until stabilization or until the outcome is known, unless the subject is documented as “lost to follow-up”. 
u Long-term follow-up for survival, every 3 months after the safety follow-up visit or last PFS follow-up visit (may be performed by phone contact). 
v For patients with accessible lesions tumor sample on biopsy at the time of progressive disease 
 
** Beyond 2 years of treatment and based on the clinical judgement of the investigator the patient could continue to receive study treatments.

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APPENDIX IV: Assessment of Efficacy According to RECIST 1.1 
 
The assessment of efficacy is based on RECIST (version 1.1) {Eisenhauer E.A., 2009}  
Tumor response will be evaluated by preferably CT (or MRI) of the head and neck, chest, 
abdomen and all other known sites of disease (e.g. pelvis, if applicable) every 6 weeks until 
documented progression or for a period of 9 months after start of study treatment, whichever 
occurs first. Beyond 9 months of treatment, the evaluations will be performed every 12 weeks 
until documented progression. 
The same schedule of tumor evaluation will be applied for patients who stopped the study 
treatment for any reason other than progressive disease. 
 
All patients will be followed off treatment for further antineoplastic therapies, and for survival 
on a 3-monthly basis until death, lost to follow-up or withdrawal of consent. 
 
Same definitions and rules apply for method of assessment, measurability of tumor and baseline 
documentation of target and non-target lesions with RECIST 1.1. 
 
1 
Measurability of tumor  
 
All measurements should be recorded in metric notation (mm). 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable. 
Lymph nodes that have a short axis <10mm at baseline are considered non-pathological and 
should not be recorded or followed. 
 
If no measurable lesions are identified at baseline, the patient will not be allowed to enter the 
study. 
 
1.1. Measurable 
 
For tumor lesions: the longest diameter in the plane of measurement has to be recorded with 
a minimum size of 10mm by CT scan when CT scan slice thickness is no greater than 5mm. 
 
For nodal lesions: at baseline and in the follow-up, only the short axis of lymph node will be 
measured and followed. To be considered pathologically enlarged and measurable, a lymph 
node must be > 15 mm in short axis when assessed at baseline.  
 
1.2. Non measurable 
 
Non measurable lesions are defined as all other lesions present at baseline, including small 
lesions (longest diameter < 10 mm or pathological lymph node with ≥ 10 mm to < 15 mm short 
axis) as well as truly non measurable lesions (i.e., pleural effusion). 
 
 
 

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2 
Baseline documentation of target and non-target lesions 
 
At baseline, preferably CT (or MRI) of the head and neck, chest, abdomen and all other known 
sites of disease (e.g. pelvis, if applicable) are required. In case of bone pain, an adequate 
radiological and/or isotopic exploration is to be performed to research bone metastases. 
 
All baseline evaluations should be performed as closely as possible and never more than 21 
days before starting the study treatment. Each lesion reported must be uniquely and sequentially 
numbered on the eCRF, even if it resides in the same organ, from baseline and throughout the 
study. 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified as 
target and non-target lesions. 
 
2.1. Target lesions 
 
All measurable lesions (nodal or non-nodal) up to a maximum of 5 lesions in total (and a 
maximum of 2 per organ), should be identified as target lesions and will be recorded and 
measured at baseline. Target lesions should be selected on the basis of their size, be 
representative of all organs involved and should be those that lend themselves to reproducible 
and repeated measurements (clinical lesions should be avoided for target lesion evaluation). 
 
2.2. Non-target lesions 
 
All other lesions, including pathological lymph nodes, are considered non-target lesions. 
Measurements of these lesions are not required and these lesions should be followed as 
“present”, “absent” or “worsening” throughout the study. Multiple non-target lesions involving 
the same organ can be assessed as a group and recorded as a single item (i.e., multiple liver 
metastases). Each non-target lesion identified at baseline should be assessed at each subsequent 
evaluation and be recorded in the eCRF. 
 
Tumor markers will not be used as non-target lesions. 
 
3 
Tumor evaluation according to RECIST 1.1 
 
To assess tumor response, the sum of the longest diameters for all target lesions (and short axis 
for nodal lesions) will be calculated at baseline and throughout the study. At each assessment, 
response is evaluated first separately for the target lesions and non-target lesions identified at 
baseline. These evaluations are then used to calculate the overall lesion response considering 
the target and non-target lesions as well as the presence or absence of new lesions. 
 
3.1 
Determination of target lesions response 
 
- Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
- Partial Response (PR): Decrease of at least 30% in the sum of the diameters of target 
lesions, taking as reference the baseline sum of diameters. 
- Progressive Disease (PD): Increase of at least 20% in the sum of diameters of target lesions 
and new lesions, taking as reference the smallest sum on study (including baseline 
evaluation). In addition to the relative increase of 20%, the sum must also demonstrate an 

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absolute increase of at least 5 mm. The appearance of one or more new lesions is also 
considered as progression. 
- Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD. 
- Not Evaluated (NE): Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a different method than baseline. The 
only exception is if the SLD of the evaluable target lesions already qualifies for PD. In this 
case, the Target Response will be PD. 
 
Notes for lymph nodes as target lesions 
 
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as baseline), even if the nodes regress to 
below 10mm on study (defined as a normal lymph node). The actual short axis measurement of 
the nodes is to be included in the sum of target lesions. 
This means also that when lymph nodes are included as target lesions, the sum of lesions may 
not be zero even if CR criteria are met, since a normal lymph node is defined as having a short 
axis < 10 mm. 
Following a CR, a PD can subsequently only be assigned for target lesion response if either a 
non-nodal lesion reappears or if the absolute sum of the remaining nodal target lesions increases 
by at least 5mm and at least one of those remaining lesions are at least 10mm in size. 
 
Target lesions that become too small to measure 
 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even very small (e.g., 2 mm). However, 
if it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. If the lesion is believed to be present but too small to measure a 
default value of 5 mm according to the slice thickness should be assigned. However, if the 
radiologist is able to provide an actual measure, that should be recorded even if it is below 
5 mm. 
 
Lesions that split or coalesce  
 
In some circumstances, disease that is measurable as a target lesion at baseline and appears to 
be one mass can split and become two or more smaller sub-lesions. When this occurs, the 
diameters (long axis for non-nodal lesions; short axis for nodal lesions) of the two split lesions 
should be added together and the sum recorded in the diameter field on the eCRF under the 
original lesion number. This value will be included in the sum of diameters when deriving target 
lesion response. The individual split lesions will not be considered as new lesions, and will not 
automatically trigger a PD designation. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesions. If the lesions have truly 
coalesced such that they are no longer separable, the maximal diameter (long axis for non-nodal 
lesions; short axis for nodal lesions) for “merged lesion” should be used when calculating the 
sum of diameters for target lesions. On the eCRF, the diameter of the “merged lesion” should 
be recorded for the size of one of the original lesions while a size of 0 mm should be entered 
for the remaining lesion numbers which have coalesced. 
 

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Reappearance of lesions 
 
If the lesion appears at the same anatomical location where a target lesion had previously 
disappeared, it is advised that the time point lesion disappearance be re-evaluated to make sure 
that the lesion was not actually present and/or not visualized for technical reasons in this 
previous assessment. If it is not possible to change the 0 value, then the investigator/radiologist 
has to decide between the following possibilities: 
- The lesion is a new lesion, in which case the overall assessment will be considered as PD. 
- The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
lesion has to be entered in the eCRF with the same numbering as baseline and the tumor 
assessment will remain based on the sum of tumor measurements as presented above. Proper 
documentation should be available to support this decision. 
 
For those patients who have only one target lesion at baseline, the reappearance of the target 
lesion which disappeared previously, even if still small, is considered a PD. 
 
Missing measurements 
 
In cases where measurements are missing for one or more target lesions, it is sometimes still 
possible to assign PD if the sum of the diameters of the remaining lesions qualifies already for 
a PD. However, in other cases where a PD cannot definitely be attributed, the target lesion 
response would be NE. 
 
3.2 
Determination of non-target lesions response 
 
- Complete Response (CR): Disappearance of all non-target lesions. In addition, all lymph 
nodes assigned as non-target lesions at baseline must be non-pathological in size (<10mm in 
short axis).  
- Incomplete Response/Stable Disease (SD): neither CR nor PD. 
- Progressive disease (PD): Unequivocal progression of existing non-target lesions.  
- Not All Evaluated (NE): Progression has not been documented and one or more non-target 
lesions have not been assessed or have been assessed using a different method than baseline 
not allowing a reliable comparison. 
 
To achieve “unequivocal progression” on the basis of the non-target disease, there must be an 
overall level of substantially worsening in non-target disease such that, even in the presence of 
CR, PR or SD in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A “modest” increase in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. The designation of 
progression solely on the basis of change in non-target disease in the face of CR, PR or SD of 
target disease will therefore be extremely rare. 
 
3.3 
New lesions 
 
The appearance of a new lesion is not always associated with PD. A lesion identified on a 
follow-up assessment in an anatomical location that was not scanned at baseline is also 
considered a new lesion. 
 

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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If at the next scheduled 
assessment, PD is confirmed, the date of progression would be the earlier date when PD was 
suspected. 
 
3.4 
Evaluation of overall lesion response according to RECIST 1.1 
 
The evaluation of overall response at each assessment is a composite of the target lesions 
response, non-target lesions response and presence of new lesions as shown below. 
 
Overall response by time point (RECIST 1.1) 
Target lesions 
Non-target lesions 
New lesions Overall response 
CR 
CR 
No 
CR1 
CR 
Incomplete response/Stable disease 
Or not all evaluated (NE) 
No 
PR 
PR 
Non-PD or not all evaluated (NE) 
No 
PR1 
SD 
Non-PD or not all evaluated (NE) 
No 
SD1, 2 
Not all evaluated 
(NE) 
Non-PD or not all evaluated (NE) 
No 
Not evaluable1 
(NE) 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1 this overall lesion response also applies when there are no non-target lesions identified at 
baseline. 
²once confirmed PR is achieved, all these assessments are considered PR.  
 
If no non-target lesions are identified at baseline, the non-target lesion response at each 
assessment will be considered “not applicable” (NA). 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate / biopsy) to confirm CR. It may be sometimes 
reasonable to incorporate Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) 
scanning to complement CT in assessment of progression (especially in case of possible “new” 
lesion) or in case where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. 
 
For equivocal findings of PD (e.g., very small and uncertain new lesions, cystic changes or 
necrosis in existing lesions) treatment may continue until the next scheduled assessment. 
 
3.5 
Best overall response according to RECIST 1.1 
 
The best overall response is the best response recorded from the inclusion/ randomization until 
disease progression/recurrence (taking as reference for PD the smallest sum on study including 
baseline evaluation). 
 
The best overall response for each patient is determined from the sequence of overall lesion 
responses by time point according to the following rules:  

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Best overall response when conﬁrmation of CR and PR required. 
Overall response  
First Time 
Overall response 
 Subsequent time 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise NE 
PR 
PR 
PR 
PR 
CR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, and NE = inevaluable.  
a If a CR is truly met at ﬁrst time point, then any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, makes the disease PD at that point (since 
disease must have reappeared after CR). Best response would depend on whether minimum 
duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
ﬁrst time point. Under these circumstances, the original CR should be changed to PR and the 
best response is PR 
 
 
- CR: at least two determinations of CR at least 4 weeks apart before progression. 
- PR: at least two determinations of PR (or better) at least 4 weeks apart before progression. 
- SD: at least one SD assessment (or better) > after a minimum exposure of 5 weeks. 
 
 
 

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APPENDIX V: Avelumab Summary of Safety Profile 
Extract of the Bavencio Summary of Product Characteristics (SmPC) dated 19 October 2022 
 

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