A Randomized, Double-Blind Placebo-Controlled, Phase 3 Study of Debio 1143 in Combination With Platinum-Based Chemotherapy and Standard Fractionation Intensity-Modulated Radiotherapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck, Suitable for Definitive Chemoradiotherapy (TrilynX)
Phase: PHASE3
Conditions: Squamous Cell Carcinoma of the Head and Neck
Sponsor: EMD Serono Research & Development Institute, Inc.

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STUDY PROTOCOL 
A randomized, double-blind placebo-controlled, Phase 3 study of Debio 1143 in combination 
with platinum-based chemotherapy and standard fractionation intensity-modulated 
radiotherapy in patients with locally advanced squamous cell carcinoma of the head and 
neck, suitable for definitive chemoradiotherapy (TrilynX) 
 
Investigational 
Medicinal Product 
Xevinapant (also known as Debio 1143) 
International 
Nonproprietary Name 
Xevinapant 
Study Numbers: 
Debio 1143-SCCHN-301 
MS202359_0006 
EudraCT Number: 
2020-000377-25 
Current Protocol 
Version: 
V13.0 dated 18 March 2024, including amendments 1-12.0 
Previous Protocol 
Version(s): 
V12.0 dated 29 February 2024, including amendments 1-11.0 
V11.0 dated 02 January 2024, including amendments 1-10.0 
V10.0 dated 11 April 2023, including amendments 1-9.0 
V9.0, dated 10 May 2022, including amendments 1-8.1 
V8.1-CHN, dated 31 January 2022, including amendments 1-8.0 
V8.0, dated 08 November 2021, including amendments 1-7.2 
V7.2-JPN, dated 13 October 2021, including amendments 1-7.1 
V7.1-JPN, dated 20 September 2021, including amendments 1-7.0 
V7.0, dated 28 June 2021, including amendments 1-6 
V6.0, dated 07 December 2020, including amendments 1-5 
V5.0, dated 06 December 2020, including amendments 1-4 
V4.0, dated 23 July 2020, including amendments 1-3 
V3.0, dated 02 July 2020, including amendments 1 and 2 
V2.0, dated 12 May 2020, including amendment 1 
V1.0, dated 02 April 2020, initial protocol 
Sponsor: 
Affiliates of Merck KGaA, Darmstadt, Germany 
For all countries, except the US and Canada: 
Merck Healthcare KGaA, Darmstadt, Germany 
an affiliate of Merck KGaA, Darmstadt, Germany 
Frankfurter Str. 250 
64293 Darmstadt, Germany 
In the US and Canada: 
EMD Serono Research & Development Institute, Inc. 
an affiliate of Merck KGaA, Darmstadt, Germany 
45A Middlesex Turnpike 
Billerica, MA, 01821, USA 
Local Sponsor for Sites in Japan: 
Merck Biopharma Co., Ltd. Japan 
an affiliate of Merck KGaA, Darmstadt, Germany 
Arco Tower, 1-8-1 Shimomeguro 
Meguro-ku, Tokyo 153-8926, Japan 
 
 
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Protocol Amendment Summary of Changes 
Protocol History 
Version Number 
Type 
Version Date 
13.0 
Global amendment 
18 March 2024 
12.0 
Global amendment 
29 February 2024 
11.0 
Global amendment 
02 January 2024 
10.0 
Global amendment – Urgent Safety Measure 
11 April 2023 
9.0 
Global amendment 
10 May 2022 
8.1 
Local amendment for China  
31 January 2022 
8.0 
Global amendment issued by Merck KGaA, Darmstadt, 
Germany; see Section 13.10 
08 November 2021 
7.2 
Local amendment for Japan; see Section 13.10 
13 October 2021 
7.1 
Local amendment for Japan; see Section 13.10 
20 September 2021 
7.0 
Global amendment issued by Debiopharm; see Section 
13.10.1.1.6  
28 June 2021 
6.0 
Global amendment issued by Debiopharm; see Section 
13.10.1.1.5 
07 December 2020 
5.0 
Global amendment issued by Debiopharm; see Section 
13.10.1.1.4 
06 December 2020 
4.0 
Global amendment issued by Debiopharm; see Section 
13.10.1.1.3 
23 July 2020 
3.0 
Global amendment issued by Debiopharm; see Section 
13.10.1.1.2 
02 July 2020 
2.0 
Global amendment issued by Debiopharm; see Section 
13.10.1.1.1 
12 May 2020 
1.0 
Original Protocol 
02 April 2020 
 
 
 
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Protocol Version 13.0 (18 March 2024) 
Overall Rationale for the Amendment 
This amendment corrects a rendering issue that duplicated Table 10-4 in Section 10.2.2.2. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 10.2.2.2, Table 
10-4 
Corrected duplication of Table 10-4 in 
rendering. 
Technical glitch caused table to be repeated. 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENT  
TABLE OF CONTENT 
4 
LIST OF TABLES 
9 
LIST OF FIGURES 
10 
ABBREVIATIONS 
10 
1. 
PROTOCOL SUMMARY 
13 
1.1. 
Synopsis ............................................................................................................. 13 
1.2. 
Study Diagram and Flow ..................................................................................... 22 
1.3. 
Schedule of Assessments ................................................................................... 24 
2. 
INTRODUCTION 
32 
2.1. 
Study Rationale .................................................................................................. 32 
2.2. 
Background ........................................................................................................ 32 
2.3. 
Risk/Benefit Assessment .................................................................................... 35 
2.3.1. 
Known Potential Risks ...................................................................................... 35 
2.3.2. 
Known Potential Benefits .................................................................................. 35 
2.3.3. 
Risk-Benefit Assessment .................................................................................. 36 
3. 
OBJECTIVES AND ENDPOINTS 
36 
4. 
STUDY DESIGN 
44 
4.1. 
Study Design and Overview ................................................................................ 44 
4.2. 
Scientific Rationale for Study Design .................................................................. 46 
4.3. 
Justification for Study Treatment Dose and Regimen .......................................... 46 
5. 
STUDY POPULATION 
48 
5.1. 
Inclusion Criteria ................................................................................................. 48 
5.2. 
Exclusion Criteria ................................................................................................ 50 
5.3. 
Lifestyle Considerations ...................................................................................... 51 
5.4. 
Screen Failures ................................................................................................... 52 
5.5. 
Strategies for Recruitment and Retention ........................................................... 52 
6. 
STUDY INTERVENTION 
53 
6.1. 
Study Intervention Administration ........................................................................ 53 
6.1.1. 
Study Intervention Description........................................................................... 53 
6.1.2. 
Dosing and Administration ................................................................................ 54 
6.1.2.1. 
Xevinapant or Matched Placebo ................................................................. 54 
6.1.2.2. 
Chemotherapy ............................................................................................ 69 
6.1.2.3. 
Radiotherapy .............................................................................................. 71 
6.2. 
Preparation/Handling/Storage/Accountability ...................................................... 73 
6.2.1. 
Acquisition and Accountability ........................................................................... 73 
6.2.2. 
Formulation, Appearance, Packaging, and Labeling ......................................... 73 
6.2.2.1. 
Formulation, Appearance, Packaging ......................................................... 74 
6.2.2.2. 
Labeling ..................................................................................................... 74 
6.2.3. 
Product Storage and Stability ............................................................................ 74 
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6.2.4. 
Preparation ....................................................................................................... 74 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ................................... 75 
6.4. 
Study Intervention Compliance ........................................................................... 76 
6.5. 
Prior, Concomitant, and Subsequent Therapy ..................................................... 77 
6.5.1. 
Permitted Concomitant Medications .................................................................. 77 
6.5.1.1. 
Antiemetics................................................................................................. 77 
6.5.1.2. 
SARS-CoV-2 Vaccination ........................................................................... 78 
6.5.2. 
Medications to be Used with Caution with Xevinapant or Matched Placebo ...... 78 
6.5.3. 
Prohibited Concomitant Medications ................................................................. 80 
6.5.3.1. 
Prohibited Medications with Xevinapant or Matched Placebo ..................... 80 
6.5.3.2. 
Recombinant Human Erythropoietin and Derivates .................................... 82 
6.5.3.3. 
Prohibited or Concomitant Use of Traditional Chinese Medicines ............... 83 
6.5.3.4. 
Prohibited Medications and Medications to be Used with Caution with Cisplatin or 
Carboplatin .................................................................................................................. 83 
6.5.3.5. 
Use of Other Investigational Agents and Devices ....................................... 83 
6.5.3.6. 
Use of Anticancer Treatments .................................................................... 83 
6.5.4. 
Rescue Therapy and Supportive Care .............................................................. 84 
6.5.4.1. 
Rescue Therapy ......................................................................................... 84 
6.5.4.2. 
Supportive Care ......................................................................................... 84 
7. 
STUDY INTERVENTION DISCONTINUATION, END OF STUDY AND EARLY STUDY 
TERMINATION 
85 
7.1. 
Study Intervention Discontinuation ...................................................................... 85 
7.2. 
End of Study ....................................................................................................... 86 
7.3. 
Premature Study Withdrawal (Participant Level) ................................................. 86 
7.4. 
Early Study Termination by the Sponsor, Steering Committee, the Investigator, the 
IEC/IRB or the Regulatory Agencies ................................................................... 87 
7.5. 
Lost to Follow-Up ................................................................................................ 87 
7.6. 
Participant Replacement ..................................................................................... 87 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
88 
8.1. 
Screening Procedure .......................................................................................... 88 
8.1.1. 
Baseline Disease Characteristics and Assessments ......................................... 88 
8.1.2. 
HPV Status in Participants with OPC ................................................................ 89 
8.1.3. 
Highly Effective Contraceptive Measures and Pregnancy Test .......................... 89 
8.2. 
Efficacy Assessments ......................................................................................... 90 
8.2.1. 
Radiological Assessment .................................................................................. 90 
8.2.2. 
Clinical Assessment .......................................................................................... 91 
8.3. 
Safety Assessments ........................................................................................... 93 
8.3.1. 
Physical Examination ........................................................................................ 93 
8.3.2. 
Vital Signs and ECOG Performance Status....................................................... 93 
8.3.3. 
Nutritional Status ............................................................................................... 93 
8.3.4. 
Dental Examination ........................................................................................... 94 
8.3.5. 
Audiometry ........................................................................................................ 94 
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8.3.6. 
Electrocardiograms ........................................................................................... 94 
8.3.7. 
Laboratory Tests: Hematology, Biochemistry, Urinalysis, Pregnancy Tests....... 96 
8.3.8. 
Participant Diary .............................................................................................. 100 
8.3.9. 
Concomitant and Subsequent Neoplastic Medications .................................... 100 
8.3.10. Adverse Event Monitoring ............................................................................... 100 
 
 
 
 
 
 
 
 
8.5. 
Biological Specimen Collection ......................................................................... 101 
8.5.1. 
Estimated Volume of Blood Samples .............................................................. 101 
8.5.2. 
Tumor Biopsy Samples ................................................................................... 102 
8.6. 
Health-Related Quality of Life Assessments ..................................................... 102 
8.7. 
Healthcare Resource Utilization Assessment .................................................... 103 
9. 
ADVERSE EVENTS 
103 
9.1. 
Definitions and Assessment Criteria ................................................................. 104 
9.1.1. 
Definition of Adverse Events ........................................................................... 104 
9.1.2. 
Definition of Serious Adverse Events .............................................................. 105 
9.1.3. 
Definition of Adverse Events of Special Interest .............................................. 105 
9.1.4. 
Definition of Adverse Event Reporting Period .................................................. 107 
9.1.5. 
Assessment of Relationship with Study Treatment(s) ...................................... 107 
9.1.6. 
Assessment of Severity of Adverse Events ..................................................... 108 
9.2. 
Procedures for Recording Adverse Events ....................................................... 108 
9.2.1. 
Diagnosis Versus Signs and Symptoms .......................................................... 109 
9.2.2. 
Adverse Events Occurring Secondary to Other Events ................................... 109 
9.2.3. 
Persistent or Recurrent Adverse Events .......................................................... 109 
9.2.4. 
Abnormal Laboratory Values ........................................................................... 109 
9.2.5. 
Deaths ............................................................................................................ 110 
9.3. 
Procedure for Reporting Serious Adverse Events to the Sponsor ..................... 110 
9.3.1. 
Follow-up of Serious Adverse Events .............................................................. 111 
9.3.2. 
Procedure for SAE Communication ................................................................. 111 
9.4. 
Other Events Requiring Immediate Reporting ................................................... 112 
9.4.1. 
Overdose ........................................................................................................ 112 
9.4.2. 
Pregnancy ....................................................................................................... 112 
10. 
STATISTICAL CONSIDERATIONS 
114 
10.1. 
Statistical Hypotheses ....................................................................................... 115 
10.1.1. Primary Hypothesis ......................................................................................... 115 
10.1.2. Secondary Efficacy Hypothesis ....................................................................... 115 
10.2. 
Sample Size Determination ............................................................................... 116 
10.2.1. Sample Size .................................................................................................... 116 
10.2.2. Robustness of Sample Size ............................................................................ 118 
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10.2.2.1. Robustness of Sample Size for Event-free Survival .................................. 118 
10.2.2.2. Robustness of sample size for overall survival ......................................... 119 
 
10.3. 
Analysis Populations ......................................................................................... 119 
10.4. 
Statistical Analyses ........................................................................................... 120 
10.4.1. General Approach ........................................................................................... 120 
10.4.2. Analysis of the Primary Efficacy Endpoint ....................................................... 120 
10.4.3. Analysis of the Secondary Efficacy Endpoints ................................................. 121 
10.4.3.1. Overall Survival ........................................................................................ 121 
10.4.3.2. Progression-free Survival ......................................................................... 122 
10.4.3.3. Locoregional Control ................................................................................ 122 
10.4.3.4. Duration of Response ............................................................................... 123 
10.4.3.5. Complete Response Rate ........................................................................ 123 
10.4.3.6. Overall Response Rate ............................................................................ 124 
10.4.3.7. Proportion of Participants with Radical Salvage Surgery .......................... 124 
10.4.3.8. Time to Subsequent Systemic Cancer Treatment..................................... 124 
10.4.3.9. HRQL Assessment ................................................................................... 124 
10.4.4. Safety Analyses .............................................................................................. 125 
10.4.4.1. Adverse Events ........................................................................................ 125 
10.4.4.2. Laboratory Parameters ............................................................................. 125 
10.4.4.3. Vital Signs Parameters ............................................................................. 125 
10.4.4.4. Extent of Exposure ................................................................................... 126 
 
10.4.6. Baseline Descriptive Statistics......................................................................... 126 
10.4.7. Planned Analyses ........................................................................................... 126 
10.4.8. Subgroup Analyses ......................................................................................... 128 
 
11. 
ETHICAL, REGULATORY AND OPERATIONAL CONSIDERATIONS 
130 
11.1. 
Ethics ................................................................................................................ 130 
11.1.1. Informed Consent Process .............................................................................. 130 
11.1.2. Independent Ethics Committees and Institutional Review Boards ................... 130 
11.2. 
Study Governance and Study Committees ....................................................... 131 
11.2.1. Independent Data Monitoring Committee / Firewall Team ............................... 131 
11.2.2. Quality Assurance Review Center ................................................................... 131 
11.2.3. Trial Steering Committee ................................................................................. 132 
11.2.4. Blinded Independent Review Committee ......................................................... 132 
11.3. 
Data Collection and Quality Assurance ............................................................. 133 
11.3.1. Clinical Monitoring ........................................................................................... 133 
11.3.2. Future Use of Stored Specimens and Data ..................................................... 133 
11.3.3. Quality Assurance and Quality Control ............................................................ 133 
11.3.3.1. Sponsor Audits ......................................................................................... 133 
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11.3.3.2. Regulatory Agency Inspections ................................................................ 134 
11.3.4. Data Handling and Record Keeping ................................................................ 134 
11.3.4.1. Confidentiality and Privacy ....................................................................... 134 
11.3.4.2. Data Management and Validation ............................................................ 134 
11.3.4.3. Data Reporting and Electronic Case Report Forms .................................. 135 
11.3.4.4. Study Records Retention .......................................................................... 135 
11.4. 
Protocol Deviations ........................................................................................... 135 
11.5. 
Changes in the Conduct of the Study ................................................................ 135 
11.5.1. Public Health Emergencies ............................................................................. 135 
11.6. 
Publication and Data Sharing Policy ................................................................. 136 
11.7. 
Insurance Policy ............................................................................................... 137 
12. 
REFERENCES 
138 
13. 
APPENDICES 
143 
13.1. 
ECOG Performance Status ............................................................................... 143 
13.2. 
Cisplatin Administration .................................................................................... 143 
13.3. 
Cisplatin Hydration Guidelines .......................................................................... 146 
13.4. 
HRQL Questionnaires ....................................................................................... 148 
13.4.1. EORTC QLQ-HN35 ......................................................................................... 148 
13.4.2. EORTC QLQ-C30 ........................................................................................... 148 
 
13.5. 
Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 Applied to this Study in 
Locally Advanced SCCHN ................................................................................ 150 
13.6. 
Audiometry Assessment (Specific for investigational sites in France) ............... 157 
13.7. 
Conduct of The Study during the COVID-19 Pandemic (Specific for Investigational 
Sites in Germany) ............................................................................................. 158 
13.8. 
Country-Specific Amendment for Japan ............................................................ 161 
13.9. 
Country-Specific Amendment for China ............................................................ 164 
13.10. Protocol Amendment History ............................................................................ 166 
13.10.1. Protocol Amendments 1 through 6 .................................................................. 176 
13.10.1.1. Protocol Amendment History Prior to Merck KGaA Sponsorship .............. 176 
13.11. Sponsor Signature Page ................................................................................... 187 
13.12. Coordinating Investigator Signature Page ......................................................... 188 
13.13. Principal Investigator Signature Page ............................................................... 189 
 
 
 
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LIST OF TABLES  
Table 1-1 Schedule of events / flow chart: screening & treatment period ............................... 26 
Table 1-2 Treatment diagram and time window for visits ........................................................ 29 
Table 1-3 Schedule of events / flow chart: follow-up visits ...................................................... 30 
Table 3-1 Objectives, endpoints and statistical considerations ............................................... 37 
Table 6-1 Xevinapant/matched placebo and platinum-based chemotherapy dose modifications after 
an AE related to study treatment(s), during combination treatment period (C1 to C3) 
(recommendations unless otherwise specified) ................................................... 57 
Table 6-2 Xevinapant/matched placebo dose modifications after an AE related to study 
treatment(s), during monotherapy treatment period (C4 to C6) (recommendations 
unless otherwise specified) .................................................................................. 67 
Table 6-3 Radiation therapy scheme ...................................................................................... 71 
Table 6-4 Formulation, appearance and packaging of investigational treatments: xevinapant and 
platinum-based chemotherapy ............................................................................. 74 
Table 6-5 Anesthetic and analgesic drugs to be used with xevinapant under close medical 
monitoring............................................................................................................ 79 
Table 6-6 Other drugs to be used with xevinapant under close medical monitoring ............... 79 
Table 6-7 Prohibited inhibitors and inducers of P-gp with xevinapant/matched placebo ......... 80 
Table 6-8 Prohibited CYP3A4 low therapeutic index drugs or sensitive substrates with xevinapant
 ............................................................................................................................ 81 
Table 8-1 ECG collection plan ................................................................................................ 94 
Table 8-2 Assessments to be performed by a central laboratory or by a local laboratory according to 
study visit............................................................................................................. 96 
Table 8-3 Assessments to be performed by a central laboratory designated by the Sponsor . 99 
Table 8-4 Biological specimens collected during the study ................................................... 102 
Table 9-1 Causal Attribution Guidance ................................................................................. 108 
Table 9-2 Adverse Event Grading (Severity) Scale .............................................................. 108 
Table 10-1 Summary of Statistical Analysis Plan ................................................................. 114 
Table 10-2 Published studies used for the sample size assumptions ................................... 117 
Table 10-3 Power Versus Alternative Hazard Ratios for EFS .............................................. 118 
Table 10-4 Power Versus Alternative Hazard Ratios for Overall Survival ............................ 119 
Table 10-5 Censoring rules for EFS ..................................................................................... 120 
Table 10-6 Censoring rules for progression-free survival ..................................................... 122 
Table 10-7 Censoring rules for locoregional control ............................................................. 123 
Table 10-8 Planned Efficacy Analyses and Expected Timing ............................................... 127 
Table 10-9 Operating Characteristics and Power Estimations .............................................. 128 
Table 13-1 ECOG Performance Status ................................................................................ 143 
 
 
 
 
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LIST OF FIGURES  
Figure 1-1 Study diagram ....................................................................................................... 22 
Figure 1-2 Study Flow ............................................................................................................ 23 
Figure 4-1 Study duration and estimated milestone markers .................................................. 45 
 
 
ABBREVIATIONS  
Abbreviation 
Explanation 
18F-FDG-PET 
Positron Emission Tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AJCC 
American Joint Committee on Cancer 
ALT 
ALanine aminotransferase 
ALP 
ALkaline Phosphatase 
ANC 
Absolute Neutrophils Count  
AST 
ASpartate aminoTransferase 
AUC 
Area Under the Concentration vs time curve 
BIRC 
Blinded Independent Review Committee 
C 
Cycle 
CBCDA 
Carboplatin 
CI 
Confidence Interval 
 
 
CKD-EPI 
Chronic Kidney Disease - Epidemiology Collaboration 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
Complete Response 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
CRR 
Complete Response Rate 
CRT 
ChemoRadioTherapy 
CT-scan 
Computed Tomography - Scan 
CxDx 
Cycle x Day x 
CYP 
Cytochrome P450 
D 
Day 
DDI 
Drug-Drug Interaction 
DILI 
Drug-Induced Liver Injury 
DoR 
Duration of Response 
ECG 
ElectroCardioGram  
ECOG 
Eastern Cooperative Oncology Group 
ECOG PS 
ECOG Performance Status 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
EFS 
Event-Free Survival 
eGFR 
estimated Glomerular Filtration Rate 
END 
Elective Neck Dissection  
EORTC 
European Organisation for Research and Treatment of Cancer 
EOS 
End Of Study 
EOT 
End Of Treatment 
EPO 
Erythropoietin 
 
 
E-R 
Exposure-Response 
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Abbreviation 
Explanation 
ESMO 
European Society for Medical Oncology 
G 
Grade 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GMP 
Good Manufacturing Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HD-CDDP 
High-Dose Cisplatin 
HIV 
Human Immunodeficiency Virus 
HPV 
Human Papilloma Virus 
HRQL 
Health-Related Quality of Life 
 
 
IAP 
Inhibitors of Apoptosis Proteins 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IHC 
ImmunoHistoChemistry 
IMRT 
Intensity-Modulated RadioTherapy 
INR 
International Normalized Ratio 
INN 
International Nonproprietary Name 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
i.v. 
Intravenous  
IWRS 
Interactive Web Response System 
LA-SCCHN 
Locally Advanced Squamous Cell Carcinoma of the Head and Neck 
LRC 
LocoRegional Control 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events  
NE 
Not Evaluable 
OIS 
Overall Imbalance Score 
ORR 
Objective Response Rate 
OPC 
OroPharyngeal Cancer 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
 
 
p.o. 
Per os (oral) 
PR 
Partial Response 
PRBC 
PTV 
Packed Red Blood Cells 
Planning Target Volume  
Q3W 
Every 3 Weeks 
QoL 
Quality of Life 
QTc 
QT interval corrected 
QTcF 
QT interval corrected using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
RiboNucleic Acid 
RP2D 
Recommended Phase 2 Dose 
RT 
RT-QA 
RadioTherapy 
RadioTherapy Quality Assurance 
RTPR 
Radiographic Time Point Response 
SCCHN 
Squamous Cell Carcinoma of the Head and Neck 
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Abbreviation 
Explanation 
SAE 
Serious Adverse Event 
SAF 
SAFety set 
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SMAC 
Second Mitochondrial-derived Activator of Caspases 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TNM 
Classification of malignant tumors: T=size of the primary tumor, N=regional 
lymph node involvement, M=distant metastasis 
TSC 
Trial Steering Committee  
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
 
  
 
 
Statement of Compliance 
This study will be conducted in accordance with the protocol and in compliance with the International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, the ethical principles that 
have their origin in the Declaration of Helsinki and its subsequent amendments, and applicable local 
laws and regulations. The Investigator will be responsible for the overall conduct at the study site and 
adherence to the requirements of the ICH guidelines and all other applicable local regulations. 
 
 
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1. PROTOCOL SUMMARY  
1.1. 
Synopsis  
Study title  
A randomized, double-blind placebo-controlled, Phase 3 study of Debio 1143 in combination with platinum-based 
chemotherapy and standard fractionation intensity-modulated radiotherapy in patients with locally advanced 
squamous cell carcinoma of the head and neck, suitable for definitive chemoradiotherapy (TrilynX). 
Study 
number 
MS202359 _0006 (Debio 1143-SCCHN-301) 
Study Phase 
3 
Study 
design 
This is a prospective, randomized, double-blind, placebo-controlled, multicenter, 2-arm, parallel-group Phase 3 study 
comparing the efficacy and safety of xevinapant versus matched placebo, when administered in combination with 
platinum-based chemotherapy and standard fractionation intensity-modulated radiotherapy (IMRT) in previously 
untreated patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), suitable for 
definitive chemoradiotherapy (CRT) (stage III, IVA, IVB; hypopharynx, larynx and/or human papillomavirus [HPV]-
negative oropharyngeal cancer [OPC]). 
Upon confirmation of eligibility, participants will be enrolled and randomized using dynamic allocation in a 1:1 ratio to: 
Arm A: 3 cycles of xevinapant (200 mg/day from Day 1 to 14, per cycle) + IMRT (70 Gy in 35 fractions over 7 weeks, 
2.0 Gy/fraction, 5 days/week) + high-dose cisplatin (100mg/m2 on Day 2, per cycle), followed by 3 cycles of 
monotherapy of xevinapant (200 mg/day from Day 1 to 14, per cycle). 
or 
Arm B: 3 cycles of placebo (Day 1 to 14, per cycle) + IMRT (70 Gy in 35 fractions over 7 weeks, 2.0 Gy/fraction, 
5 days/week) + high-dose cisplatin (100mg/m2 on Day 2, per cycle), followed by 3 cycles of monotherapy of placebo 
(from Day 1 to 14, per cycle). 
One cycle is composed of 3 weeks. 
The following stratification factors will be considered for randomization: Region (North America vs Western Europe vs 
Rest of the world), Primary tumor site (larynx vs other), Lymph node involvement (N0-1 vs N2 vs N3), T size (T4 vs 
other). 
Study diagram and flow are provided in Section 1.2. 
Study 
objectives 
and 
endpoints 
Primary, secondary, 
 objectives with associated endpoints are presented in the table below. 
Synopsis Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Primary 
To demonstrate superior efficacy of 
xevinapant vs placebo when added to CRT 
in LA-SCCHN. 
Event-Free Survival (EFS) as assessed by the Blinded Independent 
Review Committee (BIRC) defined as the time from randomization to 
the first occurrence of any of the following events: 
• 
Death from any cause. 
 
• 
Progression: 
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o 
Radiological, assessed per Response Evaluation Criteria in 
Solid Tumors (RECIST v1.1.) 
  or 
o 
Clinical, with or without RECIST v1.1-radiologically 
documented progression, assessed endoscopically. 
• 
Primary treatment failure before achieving a complete response 
(CR): requirement for radical salvage surgery that includes the 
primary tumor site, with documented viable tumor presenting 
anatomopathological findings even in the absence of formal 
RECIST v1.1 radiological progression. 
• 
Any radiological or clinical relapse after achieving a CR 
(locoregionally), including any event defined as locoregional 
treatment failure, even in the absence of formal radiological 
progressive disease confirmation: 
o 
Requirement for radical salvage surgery that includes the 
primary tumor site, regardless of anatomopathological findings. 
or 
o 
Elective neck dissection or biopsy, with positive viable tumor 
cells on anatomopathological findings at 22 weeks or later 
after randomization. 
• 
Second cancers unless anatomopathological findings exclude 
squamous histology. 
Note: Investigator-assessed EFS will be used for supportive analysis. 
Secondary 
To assess the efficacy of xevinapant 
compared to placebo when added to CRT 
according to additional efficacy endpoints. 
Overall survival defined as the time from randomization to death due 
to any cause. 
Progression-Free Survival (PFS) defined as the time from 
randomization to the first occurrence of progression (radiological or 
clinical, as assessed by the BIRC) or death from any cause. 
Note: Investigator-assessed PFS will be used for supportive analysis. 
 
Locoregional control defined as the time from randomization to the 
first occurrence of progression at the site of the primary tumor or the 
locoregional lymph nodes, either according to RECIST v1.1 or based 
on clinical assessment (radiological or clinical, as assessed by 
Investigator). 
Note: Will be investigated by BIRC as supportive analysis. 
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Objective response rate, defined as the proportion of participants with 
CR or partial response by RECIST v1.1, as assessed by the BIRC. 
Note: Investigator-assessed response will be used for supportive 
analysis. 
 
CR rate, defined as the proportion of participants with CR by RECIST 
v1.1, as assessed by the BIRC. 
Note: Investigator-assessed response will be used for supportive 
analysis. 
 
Duration of response defined as the time from the first evidence of 
response (partial or complete, as assessed by the BIRC according to 
RECIST v1.1) to the first occurrence of progression (radiological or 
clinical, as assessed by the BIRC) or death from any cause. 
Note: Investigator-assessed duration of response will be used for 
supportive analysis. 
Proportion of participants with radical salvage surgery (excluding 
elective neck dissection, without anatomopathological evidence of 
residual malignant cells). 
 
Time to subsequent systemic cancer treatments. 
To compare safety, tolerability, and 
treatment compliance of xevinapant vs 
placebo, when added to CRT. 
Incidence and severity of adverse events, serious adverse events 
and adverse events of special interest, changes in laboratory values, 
vital signs, and electrocardiograms according to NCI-CTCAE v 5.0. 
Extent of exposure of the different treatment agents (i.e., Xevinapant 
or matched placebo, radiotherapy [RT], chemotherapy) including: 
• 
Treatment duration. 
• 
Number of cycles. 
• 
Actual dose. 
• 
Dose intensity. 
• 
Relative dose intensity. 
• 
Incidence of treatment interruption. 
• 
Incidence of treatment reduction. 
• 
Incidence of treatment discontinuation. 
To compare the health-related quality of life 
of xevinapant vs placebo when added to 
CRT using patient-reported outcome 
questionnaires. 
Changes from baseline in: 
• 
Global Health Scale/Quality of Life and Fatigue using European 
Organisation for Research and Treatment of Cancer (EORTC) 
QLQ-C30 questionnaire. 
• 
Swallowing and Pain using EORTC QLQ-HN35 questionnaire. 
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Study 
population 
and sample 
size 
The study population includes adult patients with LA-SCCHN (stage III, IVA or IVB) with histologically confirmed 
diagnosis in at least one of the following sites: oropharynx (HPV-negative), hypopharynx and larynx. Patients should 
be previously untreated and suitable for definitive CRT as determined by a multidisciplinary oncology team, as is 
currently standard clinical practice. 
This study population will be defined by the inclusion and exclusion criteria below. No protocol waivers will be 
granted. 
Upon confirmation of eligibility, participants will be enrolled and randomized. 
Assuming a 30% screening failure rate, approximately 1000 participants will be screened worldwide at approximately 
280 sites and will undergo study related screening assessments to randomize ~700 participants. 
Note: Additional Chinese participants from China Mainland will be randomized in a China-specific extension cohort. 
Inclusion 
criteria 
The following inclusion criteria must be met during screening: 
1. 
Willing and able to sign written informed consent prior to study screening. 
2. 
Male or female ≥ 18 years of age (or based on the country legal age limit for adults) on day of signing the 
Informed Consent Form (ICF). 
3. 
Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. 
4. 
Histologically confirmed diagnosis of previously untreated LA-SCCHN patient (stage III, IVA or IVB according to 
the American Joint Committee on Cancer [AJCC]/TNM Staging System, 8th Ed.) suitable for definitive CRT, of at 
least one of the following sites: oropharynx, hypopharynx, and larynx. 
 
Note: Archival tumor sample to be provided (except for China), if available. 
5. 
Evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography 
scan or magnetic resonance imaging, based on RECIST v 1.1. 
6. 
For OPC patients, primary tumors must be HPV-negative as determined by p16 expression using 
immunohistochemistry (pathological report should be available). For OPC participants, p16 cutoff for 
determination of HPV status is defined in the protocol. 
 
Note: If the site is not able to perform HPV testing by p16 IHC, it will be evaluated by a central laboratory. 
7. 
Able to swallow liquids or has an adequately functioning feeding tube, gastrostomy or jejunostomy in place 
8. 
No hearing loss by clinical assessment or ≤ grade 2 hearing impairment (according to NCI-CTCAE v.5). 
9. 
Peripheral neuropathy < grade 2. 
10. Adequate hematologic, renal, and hepatic function as indicated by: 
• 
Estimated glomerular filtration rate ≥ 60 mL/min/1.73m² (using the Chronic Kidney Disease - Epidemiology 
Collaboration [CKD -EPI] creatinine formula). 
• 
Absolute neutrophil count ≥ 1 500 cells/μL. 
• 
Platelets ≥ 100 000 cells/μL. 
• 
Hemoglobin ≥ 9.0 g/dL (blood transfusions during screening are permitted). 
• 
AST and ALT ≤ 3.0 × upper limit of normal (ULN). 
• 
Total bilirubin ≤ 1.5 × ULN (up to 2.0 × ULN is allowed if the direct bilirubin level is normal and the elevation is 
limited to indirect bilirubin). 
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11. Women of childbearing potential (according to recommendations of the Clinical Trial Facilitation Group) must 
have a negative serum pregnancy test at screening and must not be breastfeeding. 
Women of childbearing potential must agree to use highly effective contraceptive method(s) from ICF signature 
to 6 months after the last administration of chemotherapy or 3 months after last dose of xevinapant /matched 
placebo, whichever is the latest. 
Non-sterilized males who are sexually active with a female partner of childbearing potential must agree to use 
condom and spermicide from ICF signature to 6 months after the last administration of chemotherapy or 3 
months after the last dose of xevinapant /matched placebo, whichever is the latest. Because male condom and 
spermicide is not a highly effective contraception method, it is strongly recommended that female partners of a 
male study participant use highly effective contraceptive method(s) (see Section 8.1.3) throughout this period. 
Male participants must refrain from donating sperm during the clinical study and for 6 months after the last 
administration of chemotherapy or 3 months after the last dose of xevinapant /matched placebo, whichever is 
the latest. If not done previously, cryopreservation of sperm prior to receiving chemotherapy or 
xevinapant/matched placebo is advised to male participants with a desire to have children. 
Exclusion 
criteria 
Meeting any of the following criteria at screening will render a participant ineligible for participation in the study: 
1. 
Primary tumor of nasopharynx, paranasal sinuses, nasal, or oral cavity, salivary, thyroid or parathyroid gland 
pathologies, skin or unknown primary site. 
2. 
Metastatic disease (stage IVC as per AJCC/TNM, 8th Ed.). 
3. 
Prior definitive or adjuvant RT and/or radical surgery to the head and neck region which may jeopardize the 
primary tumor irradiation plan, or any other prior SCCHN systemic treatment, including investigational agents. 
4. 
Use within 14 days prior to randomization or requirement for ongoing treatment with any drug(s) on the 
prohibited medication list.  
5. 
Treatment with an investigational agent or use of an investigational device within 4 weeks of the first dose of 
study treatment. 
6. 
Known history of infection with human immunodeficiency virus (HIV). If unknown history of HIV, an HIV 
screening test is to be performed and participants with positive serology for HIV-1/2 must be excluded. 
7 
Known chronically active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. If unknown status, the 
following tests are to be performed and participants with positive serology must be excluded: 
• 
HBV screening tests: both HBV sAg and Anti-HepB core IgG. 
• 
HCV screening tests: both HCV-antibody and positive viral load HCV-RNA by PCR. 
8. 
Other infections (viral and/or bacterial and/or mycotic) requiring systemic treatment. 
9. 
Live-attenuated vaccinations within 30 days prior to first investigational treatment administration. 
10. Ongoing uncontrolled infection requiring intravenous antibiotic therapy within 1 week prior to randomization. 
11. Known gastrointestinal disorder with clinically established malabsorption syndrome and major gastrointestinal 
surgery that may limit oral absorption. 
12. Documented weight loss of >10% during the last 4 weeks prior to randomization (unless adequate measures are 
undertaken for nutritional support), OR plasmatic albumin < 3.0 g/dL. No albumin transfusions are allowed within 
2 weeks before randomization. 
13. Active gastrointestinal bleeding, or any other uncontrolled bleeding requiring more than 2 red blood cell 
transfusions or 4 units of packed red blood cells within 4 weeks prior to randomization. 
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14. Active uncontrolled inflammatory disease (including rheumatoid arthritis, systemic lupus erythematosus, Sjögren 
syndrome, severe extensive psoriasis, and other autoimmune diseases) requiring ongoing treatment with anti-
TNF medication. 
15. Any concomitant medication known to prolong the QT interval that cannot be discontinued or replaced by safe 
alternative medication within 7 days prior to start of treatment. 
16. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: 
• 
Ongoing or history of uncontrolled or symptomatic ischemic myocardiopathy within 6 months prior to 
randomization. 
• 
Known left ventricular ejection fraction < 50%, left ventricular hypertrophy, ventricular arrhythmias, bradycardia 
(heart rate < 50 bpm). 
• 
History of myocardial infarction, or severe/unstable angina, within 6 months prior to randomization. 
• 
New York Heart Association grade ≥ 3 congestive heart failure. 
• 
Congenital long QT syndrome. 
• 
Family history of long QT syndrome. 
• 
Symptomatic pulmonary embolism within 6 months prior to randomization. 
• 
Ongoing or known history of transient ischemic attacks or stroke within 6 months prior to randomization. 
• 
QTc using Fridericia’s formula (QTcF) interval > 450 ms for males and > 470 ms for females. 
17. Symptomatic pulmonary disease requiring continuous or intermittent oxygen supply. 
18. History of another malignancy within the last 3 years prior to randomization, with the exception of completely 
resected non-melanoma cell skin cancer outside the head and neck area or completely resected stage I breast 
cancer, or completely resected in-situ non-muscular invasive bladder, cervix and/or uterine carcinomas, or T1a 
squamous cell carcinoma of the esophagus. 
19. Known contraindication to undergoing positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose 
(18F-FDG-PET) scans, and/or both contrast-enhanced MRI and contrast-enhanced CT scans. 
20. Known allergy to xevinapant, cisplatin, carboplatin, other platinum-based agent or any excipient known to be 
present in any of these products or in the placebo formulation. 
21. Non-compensated or symptomatic liver cirrhosis (Child-Pugh score: B or C). 
22. Any ongoing condition or disorder, before randomization, including drug(s) or alcohol abuse, which in the 
judgment of the Investigator would make the patient inappropriate for entry into the study or precluding his/her 
ability to comply with study procedures. 
Study 
interventio
n and 
dosing 
scheme 
The study intervention includes administration of both investigational treatments and background treatments. In the 
current protocol, xevinapant (International Nonproprietary Name: xevinapant), matched placebo, cisplatin and 
carboplatin are investigational treatments. IMRT is considered as background treatment. 
The following investigational and background treatments will be administered during the study according to 
randomization: 
Arm A: 3 cycles of xevinapant (200 mg/day from Day 1 to 14, per cycle) + IMRT (70 Gy in 35 fractions over 7 
weeks, 2.0 Gy/fraction, 5 days/week) + high-dose cisplatin (100 mg/m2 on Day 2, per cycle), followed by 3 cycles of 
monotherapy of xevinapant (200 mg/day from Day 1 to 14, per cycle). 
or 
Arm B: 3 cycles of placebo (from Day 1 to 14, per cycle) + IMRT (70 Gy in 35 fractions over 7 weeks, 2.0 
Gy/fraction, 5 days/week) + high-dose cisplatin (100 mg/m2 on Day 2, per cycle), followed by 3 cycles of 
monotherapy of placebo (from Day 1 to 14, per cycle). 
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In case of toxicity after the first cisplatin dosing, participants can be switched to carboplatin (AUC= 5 or 4 on Day 2 
of each subsequent cycle depending on the toxicity observed, see Section 6.1.2.1.2). 
Xevinapant, matched placebo and CRT will be administered as per Synopsis Figure 1 and Synopsis Figure 2. 
Synopsis Figure 1 - Treatments administered during the combination therapy period
 
Abbreviations: C: cycle; CBCDA: carboplatin; CRT: chemoradiotherapy; HD-CDDP: high-dose cisplatin; IMRT: 
intensity-modulated radiotherapy; W: week. 
One cycle is composed of 3 weeks. 
 
Synopsis Figure 2 - Treatment administered during the monotherapy period 
 
Abbreviations: C: cycle; CBCDA: carboplatin; EOT: end of treatment; HD-CDDP: high-dose cisplatin; IMRT: 
intensity-modulated radiotherapy; W: week. 
One cycle is composed of 3 weeks. 
Study 
duration 
It is expected that the total duration of the study will be around 82 months (6.8 years) (Synopsis Figure 3). 
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Participant 
duration 
Participants will be followed up until premature discontinuation from study or until the last on-study participant 
reaches his/her 60-months post-randomization visit, whichever occurs first. 
Statistical 
methods 
The following analysis sets will be used for planned analyses: Intent-to-treat, Safety, 
 analysis 
set. 
The primary hypothesis on EFS will be evaluated by comparing xevinapant with placebo in combination with CRT 
using a stratified log-rank test. The stratification factors are tumor size (T4 vs other) and lymph node involvement 
(N0-1 vs N2 vs N3). Hazard ratio will be estimated using a Cox-proportional hazard regression model adjusted for the 
randomization stratification factors. Treatment effect on other time-to-event endpoints will be estimated using Cox 
regression model adjusted for the randomization stratification factors. 
Estimation of the treatment effect on binary endpoints will be done using a logistic model adjusted for the 
randomization stratification factors. 
Descriptive statistics will be provided for safety endpoints. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Hierarchical fixed sequence testing procedure is applied to control the type I error for the interim analysis and multiple 
hypotheses testing. The overall type I error is controlled at 0.025 one-sided. An O'Brien & Fleming type α spending is 
used for the calculation of the significance levels and efficacy boundaries (p-value scale). 
With 
, the clinical study has about 90% power to detect the expected hazard ratio benefit. 
Safety and 
efficacy 
oversight 
An IDMC will be established before the randomization of the first participant to provide safety and efficacy oversight 
during the study. The review of safety and efficacy data will be performed according to an IDMC Charter that will be 
prepared before data collection start. All relevant data available from this study will be provided for these reviews. 
The responsibilities of the IDMC include: 
• 
To minimize the exposure of participants to an unsafe therapy or dose. 
• 
To make recommendations for changes in study processes where appropriate. 
• 
To advise on the need for dose adjustments because of safety issues. 
• 
To endorse continuation of the study. 
It will also be the responsibility of the IDMC to review the efficacy results at the interim analysis. 
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At any time during the study when the IDMC recommends major changes, these recommendations will be presented 
to the Trial Steering Committee. 
Further details on the membership, responsibilities and working procedures of the IDMC are described in the IDMC 
Charter, provided as a separate document in the study file. 
 
1.2. 
Study Diagram and Flow  
Figure 1-1 Study diagram  
 
Abbreviations: D: day; EFS follow-up: Event-Free Survival follow-up; OS follow-up: Overall Survival follow-up 
 
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Figure 1-2 Study Flow  
 
Abbreviations: AJCC: American Joint Committee on Cancer; Cx: Cycle x; EFS: event-free survival follow-up; EOS: end of study; EOT: 
end of treatment; EU: Europe;; HPV: human papillomavirus; HRQL: health-related quality of life (evaluated with EORTC QLQ-C30, QLQ-
HN35 
questionnaires); 
 IHC, immunohistochemistry; IMRT: intensity-modulated 
radiotherapy; LA-SCCHN: locally advanced squamous cell carcinoma of the head and neck; OPC: oropharyngeal cancer; OS: overall 
survival; Q3W: every 3 weeks. 
 
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1.3. 
Schedule of Assessments  
The schedule of the normal completion of the study visits/procedures is presented in Table 1-1. The 
description of each assessment is detailed in Section 8. It may be necessary to perform these 
assessments at unscheduled timepoints if deemed clinically necessary by the Investigator. 
Screening procedures will start once the participant has signed the informed consent form (ICF). The 
screening period will start at the ICF signature and can last up to 28 days. 
18F-FDG-PET, intravenous (i.v.) contrast-enhanced CT-scan or MRI of head and neck, and CT-scan 
of chest are only accepted if they are performed within 4 weeks before randomization. Dental 
examination, audiometry, HBV/HCV/HIV tests, and fiberoptic endoscopy performed within 2 weeks 
before ICF signature do not have to be repeated during screening. If several i.v. contrast-enhanced 
CT scans/MRI of the head and neck and CT scans of the chest are available before treatment start, 
the closest imaging prior to randomization will be used as baseline (for each participant, the same 
radiological method must be used throughout the study). Further details on imaging are provided in 
Table 1-1, Section 8.2.1. 
During screening and after randomization, laboratory assessments and pregnancy tests should be 
performed either by a local laboratory or by a central laboratory designated by the Sponsor according 
to instructions provided in Table 8-2 in Section 8.3.7. 
Results from central laboratory should be used for defining participant eligibility during screening, 
except for HBV/HCV/HIV tests that may be performed by a local laboratory within 2 weeks before ICF 
signature (see above and Table 8-2) and human papillomavirus (HPV) status by p16 IHC that may 
be obtained locally (see Section 8.1.2). 
A participant will be considered eligible to receive the study treatments after he/she has signed the 
ICF, all eligibility criteria have been met and the IMRT plan has been sent to the Radiotherapy Quality 
Assurance (RT-QA) Review Center (see Section 11.2.2). Randomization can be performed once the 
participant is considered eligible. The IMRT plan must be approved by the RT-QA Review Center 
prior to the start of the IMRT. 
Study treatment (on C1D1) should begin within 7 days after randomization. 
The End of treatment (EOT) visit will be performed 15 days (± 7days) after last study treatment 
administration (i.e., xevinapant/placebo, chemotherapy or IMRT whichever is administered last), but 
prior to the start of any subsequent anticancer therapy (see also Section 7.1). 
Study procedures must be performed according to the planned visit schedule within the permitted 
visit windows. During the treatment period, each study visit day and allowed time windows will be 
based on the C1D1 date. The treatment diagram and time windows for visits during the treatment 
period are presented in Table 1-2. 
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NOTE: Renal function monitoring must also take place 48 hours (± 12 hours) after cisplatin infusion 
(i.e. at C1D4, C2D4, C3D4) based on local laboratory assessments as shown below (see also 
Table 1-1): 
Local Laboratory Sampling 
Schedule for Renal Function Monitoring 
Creatinine, eGFR 
Sodium, potassium, calcium, magnesium 
C1D4 (within 48±12 hours from C1D2) 
C2D4 (within 48±12 hours from C2D2) 
C3D4 (within 48±12 hours from C3D2) 
In case of abnormal renal function parameter(s) or electrolyte disbalance, additional hydration and 
electrolyte replacement should be considered, as well as cisplatin dose adaptation in the next cycle. 
Adequate hydration must be maintained pre- and post-cisplatin infusion according to the following 
schedule (see Appendix 13.3 for detailed instructions): 
Pre-infusion 
Post-infusion 
2 to 12 hours prior to administration of cisplatin 
until minimum 6 hours after the administration of cisplatin 
Every attempt should be made to have each participant attend each visit as scheduled. Study 
visits/procedures performed outside of the allowed visit window will be considered as protocol 
deviations, with the exception of premature discontinuation from study treatment or withdrawal from 
the study due to reasons described in Section 7. 
The EFS follow-up period must be performed according to the planned visit schedule within the 
permitted visit windows. Participants without any progression, treatment failure, local or distant 
relapse, second cancers or death until Month 60 post-randomization, will enter the overall survival 
(OS) follow-up period after the Month 60 visit (FUP60). They will be followed for survival status only, 
at least every 3 months, until the End of Study (EOS) (see Section 7.2). Participants who progress 
according to RECIST v1.1, will enter the OS follow-up period at time of the event and will be followed 
up for survival status at least every 3 months, until the EOS (see Section 7.2). 
In case of premature discontinuation of treatment in participants without disease progression (e.g., 
unacceptable toxicity), efficacy assessments will continue to be performed until an EFS event has 
been determined or Month 60 post-randomization, whichever occurs first. 
During the EFS follow-up period and OS follow-up period, each study visit day and allowed time 
windows will be based on the randomization date. 
After completion of the follow-up period, participants who have not discontinued the study prematurely 
will undergo the EOS assessments ([date of the 60 Month visit of the last on-study participant] 
± 2 months) and will be considered as having completed the study (see Section 7.2 in case of 
premature withdrawal). 
If the last on-study participant completes the OS follow-up (60 months after randomization), his/her 
EOS visit will be performed at the same time as his/her 60 Month visit. In case of premature 
discontinuation from the study, his/her EOS visit will be performed when he/she discontinues from 
the study. 
The EOS visit can be performed by telephone call.
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Table 1-1 Schedule of events / flow chart: screening & treatment period  
Study Period 
Section 
Scr 
Combination therapy (CRT and Xevinapant/matched placebo) period 
Monotherapy 
(xevinapant or 
matched placebo) 
period 
EOT 
visit1 
Cycles 
- 
1 
2 
3 
4 
5  
6 
Visit Label 
Scr 
C1D1 C1D2 
C1D4 C1D8 C1D15 C2D1 C2D2 C2D4 C2D8 C2D15 C3D1 C3D2 C3D4 C3D8 C3D15 C4D1 C5D1 C6D1 EOT 
Study Week 
-4 to -1 
(≤4 
weeks) 
1 
1 
1 
2 
3 
4 
4 
4 
5 
6 
7 
7 
7 
8 
9 
10 
13 
16 
20 
Study Visit Day (from 1st dose 
administration) 
-28 to -1 
(≤28 
days) 
1 
2 
4 
8 
15 
22 
23 
25 
29 
36 
43 
44 
46 
50 
57 
64 
85 
106 
134 
Cycle Visit Day 
- 
1 
2 
4 
8 
15 
1 
2 
4 
8 
15 
1 
2 
4 
8 
15 
1 
1 
1 
- 
Visit Window (days) 
- 
see footnote 2 
±12h 
 
 
±3d 
 
±12h 
 
 
±3d 
 
±12h 
 
 
±3d 
±3d 
±3d 
±7d 
Informed consent 
8.1, 
11.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor staging 
8.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived tumor biopsy3  
8.5.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
8.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, height 
8.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV, HCV, HIV tests 
8.3.7 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
5.1, 5.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization5 
6.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
8.3.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination,  
weight  
8.3.1, 
8.3.2 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
ECOG PS  
8.3.2 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Vital signs 
8.3.2 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
ECG 
8.3.6  
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nutritional status 
8.3.3 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Dental examination 
8.3.4 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Audiometry 
8.3.5 
X4 
 
 
 
 
 
(X)10 
 
 
 
 
(X)10 
 
 
 
 
(X) 10 
 
 
(X)10 
Coagulogram 
8.3.7 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Blood hematology  
8.3.7 
X 
X6, 7 
 
 
X 
X 
X7 
 
 
X 
X 
X7 
 
 
X 
X 
X 
X 
X 
X 
Blood biochemistry –  
full panel 
8.3.7 
X 
X6, 7 
 
 
 
 
X7 
 
 
 
 
X7 
 
 
 
 
X 
X 
X 
X 
Blood biochemistry–  
minimum panel 
8.3.7 
 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
Renal function monitoring14 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Pregnancy test8 
8.1.3, 
8.3.7 
X 
X6 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Urinalysis 
8.3.7 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
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Study Period 
Section 
Scr 
Combination therapy (CRT and Xevinapant/matched placebo) period 
Monotherapy 
(xevinapant or 
matched placebo) 
period 
EOT 
visit1 
Cycles 
- 
1 
2 
3 
4 
5  
6 
Visit Label 
Scr 
C1D1 C1D2 
C1D4 C1D8 C1D15 C2D1 C2D2 C2D4 C2D8 C2D15 C3D1 C3D2 C3D4 C3D8 C3D15 C4D1 C5D1 C6D1 EOT 
Study Week 
-4 to -1 
(≤4 
weeks) 
1 
1 
1 
2 
3 
4 
4 
4 
5 
6 
7 
7 
7 
8 
9 
10 
13 
16 
20 
Study Visit Day (from 1st dose 
administration) 
-28 to -1 
(≤28 
days) 
1 
2 
4 
8 
15 
22 
23 
25 
29 
36 
43 
44 
46 
50 
57 
64 
85 
106 
134 
Cycle Visit Day 
- 
1 
2 
4 
8 
15 
1 
2 
4 
8 
15 
1 
2 
4 
8 
15 
1 
1 
1 
- 
Visit Window (days) 
- 
see footnote 2 
±12h 
 
 
±3d 
 
±12h 
 
 
±3d 
 
±12h 
 
 
±3d 
±3d 
±3d 
±7d 
EORTC QLQ-C30 and 
EORTC QLQ-HN35 
questionnaires 
8.6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
18F-FDG-PET 
8.2.1 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
i.v contrast-enhanced CT-scan 
or MRI of head and neck AND 
CT-scan of chest 
8.2.1 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X13 
Clinical tumor assessment of 
ear, nose and throat 
examination and fiberoptic 
endoscopy 
8.1.1, 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xevinapant / matched placebo 
administration 
6.1.2.1, 
Table 1
-2 
 
From Day 1 to 14 
 
From Day 1 to 14 
 
From Day 1 to 14 
 
From 
Day 1 
to 14 
From 
Day 1 
to 14 
From 
Day 1 
to 14 
 
Participant diary dispensation 
8.3.8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HD-CDDP or CBCDA 
6.1.2.2, 
Table 1
-2 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
IMRT 
6.1.2.3, 
Table 1
-2 
 
5 fractions/week for 7 weeks 
 
 
 
 
 
 
EFS data collection11 
8.2 
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
Concomitant medication 
6.5 
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
Adverse events 
8.3.10, 
9 
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
SAEs and late onset AESIs 
9.1.4 
- 
X 
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Abbreviations: AESI: adverse event of special interest; CBCDA: carboplatin; CRT: chemoradiotherapy; CT-scan: computed tomography scan; d: days; CxDx: 
Cycle x Day x; ECG: electrocardiogram; eCRF: electronic case report form;  ECOG PS: Eastern Cooperative Oncology Group Performance Status; EFS: event-free 
survival; EORTC: European Organisation for Research and Treatment of Cancer; EOS: end of study; EOT: end of treatment; 
 HBV: hepatitis B virus; HCV: hepatitis C virus; HD-CDDP: high-dose cisplatin; HIV: human immunodeficiency virus; 
 HPV: 
human papilloma virus; IMRT: intensity-modulated radiotherapy; i.v.: intravenous; MRI: magnetic resonance imaging; OPC: oropharyngeal cancer; OS: overall 
survival; 
 18F-FDG-PET: positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose; Scr: screening. 
 
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1. 
The EOT visit will be performed 15 days (± 7days) after last study treatment administration (i.e., xevinapant/placebo, chemotherapy or IMRT whichever is 
administered last) but prior to the start of any subsequent anticancer therapy. 
2. 
C1D1 and C1D2 are triggered by the 1st dose administration of xevinapant/matched placebo and HD-CDDP, respectively. These visits should be performed on 
consecutive days (see also Table 1-2). 
3. 
Participant should be willing to provide an archival tumor sample for exploratory purposes (except for China), if available; it should also be used for HPV status 
definition by p16 IHC testing (in participants with OPC) if no local report is available. See Sections 8.4.2 and 8.5.2. 
4. 
18F-FDG-PET, i.v. contrast-enhanced CT-scan or MRI of head and neck, and CT-scan of chest are only accepted if they are performed within 4 weeks before 
randomization. Dental examination, audiometry, HBV/HCV/HIV tests, and fiberoptic endoscopy performed within 2 weeks before ICF signature do not have to 
be repeated during screening. 
5. 
Treatment on C1D1 should be initiated within 7 days after randomization. 
6. 
On C1D1, hematologic, renal and hepatic laboratory assessments (as required in inclusion criteria 10, Section 5) and pregnancy status (assessed by urine or 
serum test) should not be repeated locally if latest results (assessed by central laboratory) are within 7 days prior to the 1st dose administration (see also 
Table 8-2). 
7. 
On C1D1, C2D1 and C3D1, suitability for chemotherapy administration (see Section 6.1.2.2) should be checked by a local laboratory (see exception on C1D1 
in Table 8-2). Suitability for CRT administration must be documented in the participant medical record. 
8. 
Serum pregnancy test during screening will be performed by a central laboratory in women of childbearing potential. Negative pregnancy status should be 
rechecked locally (serum or urine test) on C1D1 before first dose administration if the assessment was performed more than 7 days before. After C1D1, a urine 
or serum pregnancy test should be performed by a local laboratory (see also Table 8-2). 
 
 
10. An audiometry must be performed at screening. In addition, a hearing clinical evaluation and an audiometry should be performed at C2D1 and C3D1 if clinically 
indicated (except for France, see Appendix 13.6) and at any time if clinically indicated as per institutional or national guidelines. 
11. After progression (according to RECIST v1.1), at any time during the study, participants will enter the OS follow-up period and will be followed up for survival at 
least every 3 months until EOS (see Table 1-2and Section 7.2). Survival follow-up can be performed by telephone calls. 
 
 
 
 
 
 
13. Response confirmation is not required. In case of doubt of a clinical locoregional recurrence or distant metastasis before the EOT, imaging by CT/MRI scan 
should be performed to confirm the disease progression. 
14. Renal function monitoring 48 hours (±12 hours) after cisplatin infusion (i.e at C1D4, C2D4 and C3D4) based on local laboratory assessments (see Table 8-2) 
and hydration recommendation (see Appendix 13.3 for instructions). 
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Table 1-2 Treatment diagram and time window for visits  
 
Abbreviations: C: cycle; CBCDA: carboplatin; CRT: chemoradiotherapy; EOT: end of treatment; HD-CDDP: high-dose cisplatin; IMRT: intensity-modulated 
radiotherapy; W: week. 
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a On days when IMRT and chemotherapy are to be administered, 
 
 On days when IMRT is to be administered without chemotherapy, xevinapant or 
matched placebo should be preferably administered before IMRT. 
b During the treatment period, each study visit day and allowed time windows will be based on C1D1 date. C1D1 and C1D2 are triggered by the 1st dose administration 
of xevinapant/matched placebo and HD-CDDP, respectively. These visits should be performed on consecutive days. 
Stripped gray boxes in the row “Time window for visit” represent days around a specific study visit (represented in gray in the row “Study visit day”) where the visit 
can be rescheduled (see also time windows planned in the schedule of assessments - Table 1-1). 
c Xevinapant oral solution or placebo: once daily from D1 to D14 of each cycle. Xevinapant/matched placebo should be administered orally, early in the morning, on 
an empty stomach (no food intake within 2 hours before xevinapant/matched placebo administration). Participants should fast for at least 1 hour after dosing. See 
also Section 6.1.2.1. 
d Platinum-based chemotherapy in C1, C2 and C3 (see also Section 6.1.2.2): 
HD-CDDP (100 mg/m2) as an i.v. infusion over at least 90 minutes, on the day after the 1st administration of xevinapant/matched placebo at C1. 
For participants not eligible to continue with HD-CDDP at C2 or C3: switch to CBCDA at the next scheduled chemotherapy administration. 
e IMRT should be delivered in 35 fractions over 7 weeks, 5 planned fractions weekly (solid color). If IMRT is put on hold due to safety or administrative reason, the 7 
weeks of IMRT can be administered until Study Week 9 (striped color). See also Section also 6.1.2.3. 
f The EOT visit will be performed 15 days (± 7days) after last study treatment administration (i.e., xevinapant/matched placebo, chemotherapy or IMRT whichever is 
administered last), but prior to the start of any subsequent anticancer therapy. 
 
 
 
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Table 1-3 Schedule of events / flow chart: follow-up visits  
Study Period 
Protocol
Section 
EFS FOLLOW-UP 
OS FOLLOW-UP 
Study Timing 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
FUPx1 
(where x is the 
number of 
months post-
randomization): 
At least every 3 
months  
EOS 
(date of 
Month 60 
visit of last on-
study 
participant) 
±2 months or 
premature 
study 
discontinuation 
Visit Label 
FUP7 
FUP9 FUP12 FUP15 FUP18 FUP21 FUP24 FUP27 FUP30 FUP33 FUP36 FUP42 FUP48FUP54 FUP60 
Study Month 
(post-randomization) 
7 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
42 
48 
54 
60 
Study Visit Day 
D1 of 
M7 
±2wk 
D1 of 
M9 
±2wk 
D1 of 
M12 
±2wk 
D1 of 
M15 
±2wk 
D1 of 
M18 
±2wk 
D1 of 
M21 
±2wk 
D1 of 
M24 
±2wk 
D1 of 
M27 
±2wk 
D1 of 
M30 
±2wk 
D1 of 
M33 
±2wk 
D1 of 
M36 
±2wk 
D1 of 
M42 
±2wk 
D1 of 
M48 
±2wk 
D1 of 
M54 
±2wk 
D1 of 
M60 
±2wk 
Physical examination, weight 
8.3.1, 
8.3.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
8.3.2 
X 
 
X 
 
X 
 
 X 
 
 
 
X 
 
X 
 
X 
 
 
Vital signs 
8.3.2 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Nutritional status  
8.3.3 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Audiometry2 
8.3.5 
(X) 
 
Coagulogram 
8.3.7 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood hematology 
8.3.7 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood biochemistry – full panel 
8.3.7 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
8.3.7 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EORTC QLQ-C30, EORTC QLQ-HN35 
 
 questionnaires 
8.6 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
18F-FDG-PET3 
8.2.1 
(X on 
Week 31 ± 2 weeks 
after 1st dose) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
i.v contrast-enhanced CT-scan or MRI of head 
and neck AND CT-scan of chest 4 
8.2.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical tumor assessment of ear, nose and 
throat examination and fiberoptic endoscopy 
8.3.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
EFS data collection1 
8.2 
<----------------------------------------------------------------> 
 
 
Survival status1  
8.2 
<----------------------------------------------------------------> 
At least every 3 months 
Subsequent antineoplastic therapies  
6.5 
<----------------------------------------------------------------> 
SAEs and late onset AESIs  
8.3.10, 9                                                                                  <----------------------------------------------------------------> 
Abbreviations: AESI: adverse event of special interest; CT-scan: computed tomography scan; D: day; ECG: electrocardiogram; ECOG PS: Eastern Cooperative 
Oncology Group Performance Status; EFS: event-free survival; END: elective neck dissection; EORTC: European Organisation for Research and Treatment of 
Cancer; EOS: end of study; EOT: end of treatment; 
 FUP: follow-up; 
 i.v.: intravenous; M: 
month; MRI: magnetic resonance imaging; OS: overall survival; SAE: serious adverse event; 18F-FDG-PET: positron emission tomography with 2-deoxy-2-[fluorine-
18] fluoro-D-glucose; wk: week. 
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1. 
After progression (according to RECIST v1.1) at any time during the study, participants will enter the OS follow-up period and will be followed up for survival at 
least every 3 months until EOS (see also Section 7.2). Survival follow-up can be performed by telephone calls. 
Participants without any progression, treatment failure, local or distant relapse, second cancers or death until Month 60 post-randomization, will enter the OS 
follow-up period after the visit of Month 60 (FUP60). They will be followed only for survival status, at least every 3 months until EOS (see also Section 7.2). 
Survival follow-up can be performed by telephone calls. 
Note: At progression, the participant should complete EORTC QLQ-C30, EORTC QLQ-HN35 
 questionnaires. 
2. 
An audiometry is to be performed only if clinically indicated, as per institutional or national guidelines. 
3. 
If the scan at EOT was negative (see Table 1-1 for schedule) no further 18F-FDG-PET scans should be performed. If the EOT scan was positive AND the 
participant underwent salvage surgery and END, no further 18F-FDG-PET scans should be performed. If EOT results were inconclusive AND the participant did 
not undergo salvage surgery and END, the 18F-FDG-PET scan should be repeated 12 weeks after EOT (Week 31±2weeks). 
4. 
Response confirmation is not required. 
 
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2. INTRODUCTION  
2.1. 
Study Rationale  
Squamous cell carcinoma of the head and neck (SCCHN) is the 6th most common cancer 
worldwide and more than half of the locally advanced SCCHN (LA-SCCHN) patients will have a 
tumor relapse or treatment failure within 5 years of treatment (Magnes et al. 2017). 
Definitive treatment options for locally advanced (LA)-SCCHN such as surgery can cure some 
patients, but can also lead to severe limitations in feeding (chewing and swallowing), speaking, 
and physical appearance that can impair social functioning and cause severe psychological stress 
(Hernández-Vila 2016; NCCN 2019). Aside from technological improvements in surgical technique 
and radiation delivery, no major innovations have improved care for patients with LA-SCCHN for 
years. Despite this, many patients with LA-SCCHN remain ineligible/unsuitable for tumor resection 
(NCCN 2019; Hernández-Vila 2016). 
Among conservative (non-surgical) treatments, the most widely used standard regimen in this 
setting consists of 100 mg/m2 cisplatin administered every 3 weeks (Q3W), combined with ~70 Gy 
radiation delivered in 1.8-2.0 Gy daily fractions. Although associated with increased toxicity 
compared to radiotherapy (RT) alone, this combination is also associated with increased local 
control rates and OS (Oun et al. 2018). 
Functional impairments particularly affect oropharyngeal cancer (OPC) negative for human 
papillomavirus (HPV), and non-OPC patients (Ringash et al. 2017). HPV status is considered to 
be a strong and independent prognostic factor for survival (Ang et al. 2010) and HPV-negative 
OPC patients are considered to have a worse prognosis. Those patients require more and better 
tailored options, to improve overall treatment outcomes (Marur et al. 2014; Du et al. 2019). 
Therefore, improving SCCHN therapy to enhance treatment outcomes in patients with locally 
advanced SCCHN, who are suitable for definitive chemoradiotherapy (CRT), without generating 
increased detriment to patients’ quality of life (QoL), is a priority. 
Xevinapant is an antagonist of inhibitors of apoptosis proteins (IAPs) that has been shown to have 
both chemo-radio-sensitizing and immunomodulatory potential. The current Phase 3 study aims 
to support the approval of xevinapant in untreated LA-SCCHN patients receiving standard of care 
platinum-based chemoradiation concurrently. Xevinapant may provide an improved therapeutic 
option for LA-SCCHN patients suitable for definitive CRT who are more likely to experience 
locoregional failures. 
2.2. 
Background  
Epidemiology and clinical presentation 
Head and neck cancer include a variety of epithelial tumors originating in the lip, oral cavity, 
hypopharynx, oropharynx, nasopharynx, or larynx. Worldwide, head and neck cancer accounts 
for more than 650,000 cases and 330,000 deaths annually (Bray et al. 2018). In the United States, 
head and neck cancer accounts for 3% of malignancies, with approximately 53,000 Americans 
developing head and neck cancer annually and 10,800 dying from the disease (Siegel et al. 2020). 
In Europe, there were approximately 250,000 cases (an estimated 4% of the cancer incidence) 
and 63,500 deaths in 2012 (Gatta et al. 2015). 
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Most head and neck cancers (90% to 95%) are SCCHN. Approximately two-thirds of those 
patients are diagnosed with LA-SCCHN (Denaro et al. 2016). Clinical symptoms are varied and 
include gradually progressing impairment in respiration, swallowing, and speech (Marur et al. 
2008). LA-SCCHN is a highly destructive disease, with patients tending to develop local lymph 
node metastases early, and may develop distant metastases at relatively late stages, even after 
effective local therapy (Gupta et al. 2016). The most frequent primary tumor sites eligible for 
definitive non-surgical treatment include the oropharynx, hypopharynx, or larynx. 
 
Risk factors 
Alcohol and tobacco abuse are linked to an increased risk for SCCHN cancers, largely due to 
exposure of the upper aero-digestive tract to carcinogens found in these substances. 
HPV-negative alcohol and/or tobacco-related SCCHN frequently harbors mutations of the p53 
gene and downregulation of the p16 protein. These mutations are linked to poor prognosis and 
poor survival associated with CRT resistance and treatment failures (Ang et al. 2010). Patients 
with a smoking history of more than 10 pack-years and HPV-negative OPC have a median OS 
slightly over 24 months, and the risk of death and cancer relapse increased by 1% for each 
additional pack-year of tobacco smoking (Pignon et al. 2009; Ang et al. 2010). 
OPC patients can be classified as low, intermediate, and high-risk patients, according to the 
presence of prognostic factors such as HPV status and alcohol or tobacco abuse. 
HPV infection, in particular HPV type 16 (p16), is a known risk factor for the development of 
oropharynx SCCHN, particularly in endemic regions. However, patients with HPV-negative OPC 
have a worse prognosis compared to HPV-positive patients. HPV-negative tumors in patients with 
stage III or IV oropharyngeal SCCHN were shown to be associated with a worse OS rate and 
progression-free survival (PFS) at 3 years. The 3-year rates of OS were 82.4% (95% confidence 
interval [CI], 77.2 to 87.6) in the OPC HPV-positive subgroup and 57.1% (95% CI, 48.1 to 66.1) in 
the HPV-negative subgroup while the 3-year rates of PFS were 73.7% (95% CI, 67.7 to 79.8) and 
43.4% (95% CI, 34.4 to 52.4), respectively (Ang et al. 2010). 
 
Treatments 
Multidisciplinary treatments, including surgery, RT, and chemotherapy alone or in combination 
represent the treatment options for SCCHN patients depending on the disease stage. LA-SCCHN 
disease is treated with curative intent and requires multimodality approaches including surgery 
followed by RT with or without chemotherapy. Organ-preservation approaches combining chemo- 
and RT are generally favored, with similar results compared to surgery (Wolf 1991). European 
Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) 
guidelines on treatment of SCCHN recommend the use of CRT when the tumor is unresectable 
or when surgery is not indicated (Grégoire et al. 2010; NCCN 2019). 
High-dose cisplatin (100 mg/m2) administered Q3W with concomitant RT is considered the 
standard systemic regimen in LA-SCCHN across countries, irrespective of tumor location 
(Adelstein et al. 2003; Grégoire et al. 2010). 
Despite these treatments, at least 50% of patients with LA-SCCHN develop locoregional or distant 
relapses, which are usually detected within the first 2 years of treatment (Adelstein et al. 2003; 
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NICE 2004; HAS 2009; Grégoire et al. 2010; AWMF 2012; NICE 2016; AIOM 2018; AWMF 2019). 
Around 76% of relapses at 5 years are locoregional (Pignon et al. 2009). 
The anti-PD-1 agents pembrolizumab and nivolumab have recently been approved in patients with 
recurrent/metastatic disease (Cohen et al. 2019) and are currently in development in combination 
with CRT as first-line treatment for LA-SCCHN. 
 
Health-related quality of life 
Given the potential serious physical limitations (e.g., difficulties in chewing, swallowing, speaking, 
tasting, smelling, hearing) and associated psychological distress resulting from LA-SCCHN 
treatments, improvements in therapy to enhance treatment outcomes without generating 
incremental detriment to patients’ QoL must be priorities in advancing LA-SCCHN therapy. 
Despite this significant unmet need, prospective assessments of health-related quality of life 
(HRQL) in SCCHN are scarce and cross-study comparability to inform treatment decisions is 
limited by heterogeneity in QoL research methods (Ojo et al. 2012). 
 
Clinical development of Xevinapant, an antagonist of IAPs in combination with high-dose 
cisplatin-based concomitant CRT in LA-SCCHN cancer 
Xevinapant is an orally available antagonist of IAPs that has been shown to have chemo-radio-
sensitizing, and immunomodulatory potential. 
Based on current understanding of the mechanism of action, the value of adding xevinapant to 
platinum-based conventional CRT in the treatment of previously untreated patients with non-
resected LA-SCCHN has been investigated in a Phase 1-2 study (Debio 1143-201). 
The Phase 1 part of Debio 1143-201 study (Part A or Debio 1143-201A) determined the maximum 
tolerated dose (MTD) and recommended Phase 2 dose (RP2D) to be 200 mg/day xevinapant 
once daily on Days 1 to 14 of a 3-week cycle, when used concomitantly with high-dose cisplatin-
based CRT. 
The Phase 2 part of Debio 1143-201 study (Part B or Debio 1143-201B) was a randomized, 
placebo-controlled, double-blind study. Efficacy results from the 24-month primary analysis have 
shown antitumor activity of xevinapant: patients treated with xevinapant were around 2.5 times 
more likely to have locoregional control (LRC) 18 months after completing treatment, compared 
with patients having received a placebo (see Section 2.3.2 for further details). 
Based on the preclinical evidence of xevinapant activity in SCCHN models and the primary 
analysis results of the Debio 1143-201 study, the current Phase 3 study aims to confirm the value 
of xevinapant in the treatment of previously untreated LA-SCCHN patients with hypopharynx, 
larynx and/or HPV-16 negative OPC, who are suitable for definitive CRT and are more likely to 
relapse locally. 
Please refer to the Investigator’s Brochure for further details on other non-LA-SCCHN Phase 1 
studies and on the Debio 1143-201 study. 
 
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2.3. 
Risk/Benefit Assessment  
2.3.1. 
Known Potential Risks  
In line with the postulated radio- and chemo-sensitizing effect of xevinapant, participants receiving 
xevinapant + CRT combination therapy may experience more frequent and more severe adverse 
events (AEs) related to CRT. Considering the data from the placebo-controlled study Debio 1143-
201, where xevinapant or placebo was administered in association with cisplatin and RT, an 
increased risk of nausea, mucosal inflammation, dysphagia, weight decrease, radiation skin injury, 
tinnitus, and grade 3 anemia were observed in both arms with only a slight increase of dysphagia, 
mucositis, and anemia in the xevinapant arm. Nevertheless, the predominant toxicities were 
generally mild and/or largely reversible, could be monitored by routine clinical examinations and 
were manageable by dose delay, dose reduction and/or supportive care. 
 
 
 
 
 
 
Regarding the risk of drug-drug interactions (DDIs), xevinapant is transported by P-glycoprotein 
(P-gp). Accordingly, strong P-gp inhibitors and inducers are prohibited. In addition, in vitro 
xevinapant significantly inhibits CYP3A4/5 and P-gp and has the potential to induce and down-
regulate CYP3A4/5, 2Cs, 2B6, and to down-regulate 1A2. The clinical relevance of these 
phenomena is unknown. Accordingly, narrow therapeutic range or sensitive CYP3A substrates 
are prohibited. Also, narrow therapeutic range or sensitive substrates of P-gp, CYP2Cs, 2B6 or 
1A2 should be closely monitored. 
 
 
 
 Preclinical studies also suggest that hepatitis B 
virus (HBV) titers may be reduced after treatment with SMAC mimetics by promoting the 
elimination of hepatocytes containing HBV. Candidates for xevinapant studies are therefore tested 
for HIV, HBV and hepatitis C virus (HCV) serology prior to inclusion. Any patients found to be 
positive will not be included in xevinapant studies. 
Please refer to the current version of the Investigator’s Brochure for further details on identified 
and potential risks. 
2.3.2. 
Known Potential Benefits  
Based on the potential for xevinapant to act as a chemo-, immuno- and/or radiosensitizer, the 
current development strategy for xevinapant focuses only on combination strategies with RT, 
chemotherapy, CRT or checkpoint inhibitors as accepted standard of care options whenever 
applicable. Investigated indications include solid tumors such as SCCHN, ovarian/gynecological 
cancer, non-small cell lung cancer, small cell lung cancer, and/or gastrointestinal cancers as well 
as potentially other solid tumors. 
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When xevinapant was administered in combination with CRT in LA-SCCHN patients (study Debio 
1143-201B), a statistically significant and clinically relevant improvement was observed in terms 
of LRC at 18 months and PFS, as well as a trend toward improved OS. The 24-month analysis of 
the Study 1143-201B demonstrated that the odds for LRC at 18 months after completing treatment 
is 2.5 times higher in patients (all heavy smokers, ~90% of OPC patients HPV-negative, 85% 
stage IVa or IVb) treated with xevinapant compared with patients having received a placebo (odds 
ratio [95%CI]: 2.69[1.13; 6.42]). In addition, a risk reduction of 63% for progression or death was 
observed in patients having been treated with xevinapant compared with patients having received 
a placebo, suggesting a highly statistically and clinically significant improvement in PFS (hazard 
ratio [95%CI]: 0.37[0.18; 0.76]), p=0.007. The PFS rate at 24 months after treatment start was 
72% in the xevinapant arm and 41% in placebo arm. Median PFS was not reached in the 
xevinapant arm at the 24-month analysis cut-off. Results for OS showed a consistent trend (hazard 
ratio [95%CI]: 0.65[0.32; 1.33]) although they did not reach statistical significance (p=0.243) at the 
cut-off date. Additional follow-up is ongoing and will provide more mature data (refer to the current 
version of the Investigator’s Brochure for further details). 
 
2.3.3. 
Risk-Benefit Assessment  
To date, safety results on xevinapant given in combination with CRT suggest an acceptable and 
predictable overall safety profile of the compound. Observed toxicities are mostly low grade, 
manageable and reversible, and were consistent with those expected in the target population 
receiving only CRT (with placebo). 
To mitigate identified and potential risks related to xevinapant treatment (see Section 2.3.1), the 
protocol includes close monitoring of participants for known or potential adverse reactions. 
Regular assessments include but are not limited to gastrointestinal signs and symptoms, renal 
function, and skin disorders. Laboratory values will be monitored to allow for early detection and 
treatment of any sign of hematologic toxicity as well as liver or pancreatic function abnormalities. 
Electrocardiograms (ECGs) are included in the protocol to allow QTc monitoring, as part of the 
clinical pharmacovigilance program. 
To mitigate the risk of DDIs, a list of prohibited concomitant medications as well as medications 
that should be used with caution is provided (see Section 6.5). 
 
 
 
Given the current safety and efficacy profile observed in clinical studies, suggesting a positive risk-
benefit ratio of xevinapant, further clinical research is warranted. 
 
3. OBJECTIVES AND ENDPOINTS  
The objectives and corresponding endpoints are presented in Table 3-1.
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Table 3-1 Objectives, endpoints and statistical considerations  
Objectives 
Endpoints 
Hypothesis 
Primary Analysis 
Population 
Timeframe/Time Point 
Primary 
To demonstrate superior efficacy 
of xevinapant vs placebo when 
added to chemoradiotherapy 
(CRT) in locally advanced 
squamous cell carcinoma of the 
head and neck (LA-SCCHN) 
EFS as assessed by the BIRC defined as the time from randomization 
to the first occurrence of any of the following events: 
• 
Death from any cause. 
• 
Progression: 
o 
Radiological, assessed per RECIST v1.1 
or 
o 
Clinical, with or without RECIST v1.1-radiologically 
documented progression, assessed endoscopically. 
• 
Primary treatment failure before achieving a CR: requirement for 
radical salvage surgery that includes the primary tumor site, with 
documented viable tumor presenting anatomopathological findings 
even in the absence of formal RECIST v1.1 radiological 
progression. 
• 
Any radiological or clinical relapse after achieving a CR 
(locoregionally), including any event defined as locoregional 
treatment failure, even in the absence of formal radiological 
progressive disease confirmation: 
o 
Requirement for radical salvage surgery that includes the 
primary tumor site, regardless of anatomopathological findings 
or 
o 
Elective neck dissection or biopsy, with positive viable tumor 
cells on anatomopathological findings at 22 weeks or later 
after randomization. 
• 
Second cancers unless anatomopathological findings exclude 
squamous histology. 
 
Note: Investigator-assessed EFS will be used for supportive analysis. 
Xevinapant prolongs EFS in 
previously untreated patients with 
LA-SCCHN, compared to matched 
placebo when administered in 
combination with platinum-based 
chemotherapy and intensity-
modulated radiotherapy (IMRT). 
 
Intent-to-treat 
- From randomization to 
the earliest between any 
EFS event or EOS. 
- Rate at 9, 12, 18, 24, 30 
and 36-months post-
randomization. 
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Objectives 
Endpoints 
Hypothesis 
Primary Analysis 
Population 
Timeframe/Time Point 
Secondary 
To assess the efficacy of 
xevinapant compared to placebo 
when added to CRT according to 
additional efficacy endpoints 
Overall survival (OS) defined as the time from randomization to death 
due to any cause. 
Xevinapant prolongs OS in 
previously untreated patients with 
LA-SCCHN compared to matched 
placebo when administered in 
combination with platinum-based 
chemotherapy and IMRT. 
Intent-to-treat 
- From randomization to 
the earliest between 
death or EOS 
-  Rate at 12, 24, 36, 48 
and 60 months post-
randomization. 
 
Progression-free survival (PFS) according to RECIST v1.1 defined as 
the time from randomization to the first occurrence of progression 
(radiological or clinical, as assessed by the BIRC) or death from any 
cause. 
 
Note: Investigator-assessed PFS will be used for supportive analysis. 
Xevinapant prolongs PFS in 
previously untreated patients with 
LA-SCCHN compared to matched 
placebo when administered in 
combination with platinum-based 
chemotherapy and IMRT. 
Intent-to-treat 
- From randomization to 
the earliest between 
PFS event or EOS. 
- Rate at 9, 12,18, 24, 36, 
48 and 60 months post-
randomization. 
 
Locoregional control (LRC) defined as the time from randomization to 
the first occurrence of progression at the site of the primary tumor or the 
locoregional lymph nodes, either according to RECIST v1.1 or based on 
clinical assessment (radiological or clinical, as assessed by the 
Investigator). 
 
Note: Will be investigated by BIRC as supportive analysis. 
Xevinapant prolongs LRC in 
previously untreated patients with 
LA-SCCHN compared to matched 
placebo when administered in 
combination with platinum-based 
chemotherapy and IMRT. 
Intent-to-treat 
- From randomization to 
the earliest between 
PFS event or EOS. 
- Rate at 9, 12, 18, 24, 36, 
48 and 60 months post-
randomization. 
 
ORR, defined as the proportion of subjects with CR or partial response 
by RECIST v1.1, as assessed by the BIRC. 
 
Note: Investigator-assessed response will be used for supportive 
analysis. 
Xevinapant increases the ORR in 
previously untreated patients with 
LA-SCCHN compared to matched 
placebo when administered in 
combination with platinum-based 
chemotherapy and IMRT. 
Intent-to-treat 
- From randomization to 
the earliest between 
progression, start of a 
new anticancer therapy 
for this disease or 
participant EOS. 
- Rate at 9 and 12 months 
post-randomization. 
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Objectives 
Endpoints 
Hypothesis 
Primary Analysis 
Population 
Timeframe/Time Point 
 
CR rate (CRR) defined as the proportion of participants with CR by 
RECIST v1.1, as assessed by the BIRC. 
 
Note: Investigator-assessed response will be used for supportive 
analysis. 
Xevinapant increases the CRR in 
previously untreated patietns with 
LA-SCCHN compared to matched 
placebo when administered in 
combination with platinum-based 
chemotherapy and IMRT. 
Intent-to-treat 
- From randomization to 
the earliest between 
progression, start of a 
new anticancer therapy 
for this disease or 
subject EOS. 
- Rate at 9 and 12 months 
post-randomization. 
 
Duration of response (DoR) defined as the time from the first evidence 
of response (partial or complete, as assessed by the BIRC according to 
RECIST v1.1) to the first occurrence of progression (radiological or 
clinical, as assessed by the BIRC) or death from any cause. 
 
Note: Investigator-assessed DoR will be used for supportive analysis. 
Xevinapant prolongs DoR in 
previously untreated participants 
with LA-SCCHN compared to 
matched placebo when 
administered in combination with 
platinum-based chemotherapy and 
IMRT. 
Intent-to-treat 
- From first evidence of 
response (partial or 
complete) to the earliest 
between DoR event or 
EOS. 
- Rate at 6, 12 and 24 
months post first 
evidence of response. 
 
Proportion of participants with radical salvage surgery (excluding 
elective neck dissection without anatomopathological evidence of 
residual malignant cells). 
 
Intent-to-treat 
- From randomization to 
the earliest between 
radical salvage surgery 
or EOS. 
- Rate at 9, 12, 18, 24, 36, 
48 and 60 months post-
randomization. 
 
Time to subsequent systemic cancer treatments. 
 
Intent-to-treat 
- From randomization to 
EOS 
- Rate at 12, 18, 24, 36, 
48 and 60 months post-
randomization.  
To compare safety, tolerability and 
treatment compliance of 
Incidence and severity of adverse events (AE), serious adverse events 
and adverse events of special interest, changes in laboratory values, 
vital signs, and electrocardiograms according to NCI-CTCAE v 5.0. 
 
Safety 
- From signed informed 
consent to EOS. 
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Xe vi n a p a nt  
Tril y n X  
M 2 0 2 3 5 9 _ 0 0 0 6  
 
 
 
 
4 0 /1 8 9  
 
 
O bj e cti v e s  
E n d p oi nt s  
H y p ot h e si s  
Pri m ar y A n al y si s 
P o p ul ati o n  
Ti m efr a m e/ Ti m e P oi nt  
x evi n ap ant vs pl ac e b o, w h e n 
a dd ed t o C R T  
Ext e nt of ex p os ur e of t h e diff er e nt tr e at m e nt a g e nts (i. e., x evi n a p a nt or 
m atc h e d pl ac e b o, r a di ot h er a py, c h e m ot h er a py) i ncl u di n g:  
•  
Tr e at m e nt d ur ati o n.  
•  
N u mb er of cycl es.  
•  
Act u al d os e.  
•  
D os e i nt e nsity.  
•  
R el ativ e d os e i nt e nsity.  
•  
I nci d e nc e of tr e at m e nt i nt err u pti o n. 
•  
I nci d e nc e of tr e at m e nt r e d ucti o n. 
•  
I nci d e nc e of tr e at m e nt disc o nti n u ati o n. 
 
S af ety  
- Fr o m first st u dy 
tr e at m e nt dos e t o E O T. 
T o c o mp ar e t h e h e alt h -r el at e d 
q uality of lif e of x evi n a p a nt vs 
pl ac e b o wh e n a d d e d t o C R T usi n g 
p ati e nt -r e port e d o utc o m e 
q uesti o nn air es  
C h a n g es fr o m b as eli n e i n:  
•  
 
 
 
 
. 
X evi n a p a nt is n o n -i nf eri or f or 
 
 
at M o nt h 1 2 p ost -r a n d o miz ati o n i n 
pr evi o usly u ntr e at e d p ati e nts wit h 
L A -S C C H N c o m p ar e d t o m atc h ed 
pl ac e b o wh e n a d mi nist er e d i n 
c o mbi n ati o n wit h pl ati n u m -b as e d 
c h e m ot h er a py a n d I M R T. 
I nt e nt-t o-tr e at 
- Fr o m r a nd o miz ati o n t o 
E O S.  
- At b as eli n e, St u dy W e ek 
1 0, 20 a n d m o nt hs 7, 1 2, 
2 4, 36, 4 8 a nd 6 0 p ost -
r a nd o miz ati o n. 
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Endpoints 
Hypothesis 
Primary Analysis 
Population 
Timeframe/Time Point 
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4. Study Design  
4.1. 
Study Design and Overview  
This is a prospective, randomized, double-blind, placebo-controlled, multicenter, two-arm, parallel-
group Phase 3 study comparing the efficacy and safety of xevinapant versus matched placebo, 
when administered in combination with platinum-based chemotherapy and standard fractionation 
intensity-modulated radiotherapy (IMRT) in previously untreated patients with LA-SCCHN, 
suitable for definitive CRT (stage III, IVA, IVB; hypopharynx, larynx and/or HPV-negative OPC). 
Once a participant has signed the ICF, an identification number will be assigned to him/her and 
the study related screening procedures will start. Upon confirmation of eligibility, participants will 
be enrolled and randomized in a 1:1 ratio, using dynamic allocation to: 
• 
Arm A: 3 cycles of xevinapant (200 mg/day from Day 1 to 14, per cycle) + IMRT (70 Gy in 
35 fractions over 7 weeks, 2.0 Gy/fraction, 5 days/week) + high-dose cisplatin (100 mg/m2 
on Day 2, per cycle), followed by 3 cycles of monotherapy of xevinapant (200 mg/day from 
Day 1 to 14, per cycle). 
or 
• 
Arm B: 3 cycles of placebo (from Day 1 to 14, per cycle) + IMRT (70 Gy in 35 fractions 
over 7 weeks, 2.0 Gy/fraction, 5 days/week) + high-dose cisplatin (100 mg/m2 on Day 2, 
per cycle), followed by 3 cycles of monotherapy of placebo (from Day 1 to 14, per cycle). 
In case of toxicity after the first cisplatin dosing, participants can be switched to carboplatin 
(AUC=5 or 4 on Day 2 of each subsequent cycle) depending on the toxicity observed, as per 
Table 6-1. 
The schedule of concurrent administration of xevinapant, chemotherapy and IMRT is presented 
in Table 1-1 and Table 1-2. 
Approximately 1000 participants will be screened in order to randomize approximately 700 adult 
male and female participants.  
Note: Additional Chinese participants from China Mainland will be randomized in a China-specific 
extension cohort (see Section 13.9 for further details). 
The following stratification factors will be considered for the randomization: 
• 
Region: North America vs Western Europe vs Rest of the World. 
• 
Primary tumor site: larynx vs other. 
• 
Lymph node involvement: N0-1 vs N2 vs N3. 
• 
T size: T4 vs other. 
The study includes the screening period, the treatment period (combination therapy period 
followed by the monotherapy period, each consisting of 3 cycles), the progression follow-up period 
(event-free survival [EFS] follow-up) and the OS follow-up period (see Figure 1-1 and Section 1.3 
for study schedules of assessments). Each cycle consists of 3 weeks. Participants will be followed 
up until 386 OS events are observed for the final analysis or the last on-study participant reaches 
his/her 60-months post-randomization visit or until premature discontinuation from study (see 
Section 7.2), whichever occurs first. 
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It is expected that the total duration of the study will be approximately 82 months (6.8 years), 
(Figure 4-1). 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
Special oversight committees will include external Independent Data Monitoring Committee 
(IDMC), Trial Steering Committee, and Firewall Team. The Firewall Team will be composed of a 
restricted group of individuals within the Sponsor team who are not directly involved in the study 
conduct activities. 
 
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4.2. 
Scientific Rationale for Study Design  
The target population chosen for the study is of patients for whom a significant benefit from 
treatment with xevinapant combined with the current standard of care (i.e., cisplatin-based 
standard CRT) is expected. Patients with unresectable or non-resected LA-SCCHN have the 
poorest prognosis and predominantly experience locoregional failures. 
The primary endpoint of the study is EFS, a widely accepted endpoint in LA-SCCHN studies that 
was shown to be a surrogate endpoint for OS in studies using CRT, both at the individual and 
study levels (Michiels et al. 2009; Le Tourneau et al. 2009). OS  a standard assessment of clinical 
benefit in head and neck patients with cancer, will be followed up for at least 5 years. 
In line with the radiosensitizing effect of xevinapant, both the efficacy and safety results of the 
Phase 2 study (Debio 1143-201B) suggest that xevinapant in combination with CRT result in a 
LRC and PFS benefit associated with an acceptable safety profile (see Clinical development of 
xevinapant, an antagonist of IAPs in Section 2.2). 
EFS as assessed by Investigators will be used for supportive analysis of the primary endpoint. 
Randomization is expected to compensate for possible inconsistencies in local assessments, 
hence minimizing any associated bias. 
4.3. 
Justification for Study Treatment Dose and Regimen  
Xevinapant 
In Phase 1 studies with xevinapant (Debio 1143-101 to Debio 1143-106), different dose levels 
(from 5 to 900 mg/day) and schedules (D1-5 every 2 weeks, D1-5 Q3W or D1-14 Q3W) of 
xevinapant were administered, as monotherapy or in combination with chemotherapy only, with 
CRT or with immunotherapy (please refer to the current version of the Investigator’s Brochure for 
further details on the Phase 1 and 2 studies). Doses up to 900 mg/day of xevinapant administered 
as monotherapy were tolerated and no MTD has been reached. 
Tumor penetration and target engagement (IAP1 degradation) in the tumor was shown in Phase 2 
studies Debio 1143-201 and Debio 1143-SCCHN-202. In the blood, target engagement and 
potential signs of downstream effects have been observed at all tested dose levels (100, 200 and 
300 mg/day [Days 1-14 Q3W]). Xevinapant exposures at RP2D of 200 mg/day were not 
associated with unacceptable toxicities and enabled near-maximal clinical effect in terms of tumor 
metrics. 
Based on the results of these studies, 200 mg was determined to be the MTD and was defined as 
the RP2D, administered on D1-14 of each 3-week cycle with concomitant CRT. 
 
 
 
 
 
 
 
 
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The safety profile observed in combination with CRT in the Phase 2 study indicates that even 
though some toxicities occurred more often in the xevinapant arm (anemia, mucositis, and 
dysphagia of grade 3 according to National Cancer Institute -Common Terminology Criteria for 
Adverse Events [NCI-CTCAE], which were manageable and reversible) compared to the placebo 
arm, the number of grade 4 events reported was similar in both arms. All events resolved to at 
least grade 1 soon after CRT completion with identical median times to resolution between arms. 
One grade 5 treatment-emergent adverse event (TEAE) was reported and occurred in the placebo 
arm. 
Platinum-based chemotherapy 
While there is currently no unanimous consensus on the optimal cisplatin regimen, the high-dose 
regimen of 100 mg/m² Q3W for up to 3 cycles delivered concomitantly with IMRT is generally 
considered the standard (Szturz et al. 2017), and has been widely adopted whenever patients are 
eligible for it. Hence, this regimen will be used in this study. 
In the Debio 1143-201B Phase 2 study, up to 3 cycles of high-dose cisplatin were safely 
administered concomitantly with standard fractionated IMRT and xevinapant. The median cisplatin 
dose delivered was equivalent and high in both arms (288 mg/m2). Significantly improved anti-
tumoral activity was observed in the xevinapant + CRT arm over the placebo + CRT arm (Section 
2.3.2). Therefore, the same high-dose cisplatin regimen will be used in the present study in 
combination with xevinapant and as the comparator arm. 
Nevertheless, in the current study, participants who will experience decreased estimated 
glomerular filtration rate (eGFR) (< 60 mL/min/1.73m² using the Chronic Kidney Disease - 
Epidemiology Collaboration [CKD -EPI] creatinine formula) after the first cisplatin dosing, can be 
switched to an equivalent carboplatin doses (area under the concentration vs time curve [AUC] 
5.0 Q3W). This regimen is widely accepted and was reported to have similar efficacy in a recent 
study (Wilkins et al. 2013). 
 
IMRT 
The anatomy of the head and neck is complex due to multiple elements of the digestive, 
respiratory, nervous and endocrine systems located sometimes within millimeters of each other. 
Due to the complexity of this anatomical region, large and multiple target volumes, and proximity 
to organs at risk, RT in this region is also complex. 
In addition, high-dose fractionated RT (60-72 Gy) is necessary to cure patients. Irradiation of 
critical normal tissue can cause severe discomfort with increased acute and late morbidity (Marta 
et al. 2014). Newer techniques have been developed over the past 2 decades to improve delivery 
of RT with 2 aims. Firstly, to avoid critical normal tissue to decrease toxicity (Jellema et al. 2007). 
Secondly, to administer a dose to the tumor volume high enough in order not to compromise 
control rates (Ghosh-Laskar et al. 2016). Techniques were therefore developed to shape the 
radiation beams more closely to the target volumes to spare critical tissues, hence reducing 
toxicity. 
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IMRT was implemented in the mid-1990s but only became widespread in the last decade. Closer 
shaping to the tumor contour is made possible by aiming multiple photon beams from different 
directions and with adjusted intensities. This allows better sparing of the organs at risk resulting 
in less acute and late toxicity, especially xerostomia (Ghosh-Laskar et al. 2016). Nutting et al. 
published the results of the PARSPORT study (a Phase 3 multicenter randomized controlled 
study) in 2011. They concluded that sparing the parotid glands with IMRT significantly reduced 
the incidence of xerostomia and led to recovery of saliva secretion, hence improving QoL (Nutting 
et al. 2011). According to the NCCN/ESMO guidelines, IMRT is now considered the standard of 
care for treating SCCHN. 
 
5. STUDY POPULATION  
Assuming a 30% screening failure rate, approximately 1000 participants will be screened 
worldwide at approximately 280 sites and will undergo study related screening assessments to 
randomize approximately 700 participants.   
Note: Additional Chinese participants from China Mainland will be randomized in a China-specific 
extension cohort (see Section 13.9 for further details). 
The study population include adult patients with LA-SCCHN (stage III, IVA or IVB) with 
histologically confirmed diagnosis in at least one of the following sites: oropharynx (HPV-negative), 
hypopharynx and larynx. Participants should be previously untreated and suitable for definitive 
CRT as determined by a multidisciplinary oncology team, as is currently standard clinical practice. 
This study population will be defined by the inclusion and exclusion criteria below. No protocol 
waivers will be granted. 
Upon confirmation of eligibility, participants will be enrolled and randomized. 
5.1. 
Inclusion Criteria  
The following inclusion criteria must be met during screening: 
1. Willing and able to sign written informed consent prior to study screening. 
2. Male or female ≥ 18 years of age (or based on the country legal age limit for adults) on day 
of signing the ICF. 
3. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. 
4. Histologically confirmed diagnosis in previously untreated LA-SCCHN patient (stage III, 
IVA or IVB according to the American Joint Committee on Cancer [AJCC]/TNM Staging 
System, 8th Ed.) suitable for definitive CRT, of at least one of the following sites: 
oropharynx, hypopharynx, and larynx. 
Note: Archival tumor sample to be provided (except for China), if available. 
5. Evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by 
computed tomography scan (CT-scan) or magnetic resonance imaging (MRI), based on 
RECIST v 1.1. 
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6. For OPC patients, primary tumors must be HPV-negative as determined by p16 expression 
using immunohistochemistry (IHC) (pathological report should be available). For OPC 
participants, p16 cutoff for determination of HPV status is defined in Section 8.1.2.   
Note: If the site is not able to perform HPV testing by p16 IHC, it will be evaluated by a 
central laboratory. 
6. Able to swallow liquids or has an adequately functioning feeding tube, gastrostomy or 
jejunostomy in place. 
7. No hearing loss by clinical assessment or ≤ grade 2 hearing impairment (according to NCI-
CTCAE v.5). 
8. Peripheral neuropathy < grade 2. 
9. Adequate hematologic, renal, and hepatic function as indicated by: 
• eGFR ≥ 60 mL/min/1.73m² (using the CKD-EPI creatinine formula). 
• Absolute neutrophil count (ANC) ≥ 1 500 cells/μL. 
• Platelets ≥ 100 000 cells/μL. 
• Hemoglobin ≥ 9.0 g/dL (blood transfusions during screening are permitted). 
• Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit 
of normal (ULN). 
• Total bilirubin ≤ 1.5 × ULN (up to 2.0 × ULN is allowed if the direct bilirubin level is 
normal and the elevation is limited to indirect bilirubin). 
10. Women of childbearing potential (according to recommendations of the Clinical Trial 
Facilitation Group) must have a negative serum pregnancy test at screening and must not 
be breastfeeding. 
Women of childbearing potential must agree to use highly effective contraceptive 
method(s) (see Section 8.1.3) from ICF signature to 6 months after the last administration 
of chemotherapy or 3 months after last dose of xevinapant/matched placebo, whichever is 
the latest. 
Non-sterilized males who are sexually active with a female partner of childbearing potential 
must agree to use condom and spermicide from ICF signature to 6 months after the last 
administration of chemotherapy or 3 months after the last dose of xevinapant/matched 
placebo, whichever is the latest. Because male condom and spermicide is not a highly 
effective contraception method, it is strongly recommended that female partners of a male 
study participant use highly effective contraceptive method(s) (see Section 8.1.3) 
throughout this period. 
Male participants must refrain from donating sperm during the clinical study and for 6 
months after the last administration of chemotherapy or 3 months after the last dose of 
xevinapant/matched placebo, whichever is the latest. If not done previously, 
cryopreservation of sperm prior to receiving chemotherapy or xevinapant/matched placebo 
is advised to male participants with a desire to have children. 
 
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5.2. 
Exclusion Criteria  
Meeting any of the following criteria at screening will render a participant ineligible for participation 
in the study: 
1. Primary tumor of nasopharyngeal, paranasal sinuses, nasal, or oral cavity, salivary, thyroid 
or parathyroid gland pathologies, skin or unknown primary site. 
2. Metastatic disease (stage IVC as per AJCC/TNM, 8th Ed.). 
3. Prior definitive or adjuvant RT and/or radical surgery to the head and neck region which 
may jeopardize the primary tumor irradiation plan, or any other prior SCCHN systemic 
treatment, including investigational agents (please refer to Section 6.1.1). 
4. Use within 14 days prior to randomization or requirement for ongoing treatment with any 
drug(s) on the prohibited medication list (provided in Sections 6.5.3 and 6.5.4). 
5. Treatment with an investigational agent or use of an investigational device within 4 weeks 
of the first dose of study treatment. 
6. Known history of infection with HIV. If unknown history of HIV, an HIV screening test is to 
be performed and participants with positive serology for HIV-1/2 must be excluded. 
7. Known chronically active HBV or HCV infection. If unknown status, the following tests are 
to be performed and participants with positive serology must be excluded: 
• HBV screening tests: both HBV sAg and Anti-HepB core IgG. 
• HCV screening tests: both HCV-antibody and positive viral load HCV-RNA by PCR. 
8. Other infections (viral and/or bacterial and/or mycotic) requiring systemic treatment. 
9. Live-attenuated vaccinations within 30 days prior to first investigational treatment 
administration. 
10. Ongoing uncontrolled infection requiring intravenous antibiotic therapy within 1 week prior 
to randomization. 
11. Known gastrointestinal disorder with clinically established malabsorption syndrome and 
major gastrointestinal surgery that may limit oral absorption. 
12. Documented weight loss of >10% during the last 4 weeks prior to randomization (unless 
adequate measures are undertaken for nutritional support), OR plasmatic albumin < 3.0 
g/dL. No albumin transfusions are allowed within 2 weeks before randomization. 
13. Active gastrointestinal bleeding, or any other uncontrolled bleeding requiring more than 2 
red blood cell transfusions or 4 units of packed red blood cells within 4 weeks prior to 
randomization. 
14. Active uncontrolled inflammatory disease (including rheumatoid arthritis, systemic lupus 
erythematosus, Sjögren syndrome, severe extensive psoriasis, and other autoimmune 
diseases) requiring ongoing treatment with anti-TNF medication. 
15. Any concomitant medication known to prolong the QT interval that cannot be discontinued 
or replaced by safe alternative medication within 7 days prior to start of treatment. 
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16. Impaired cardiovascular function or clinically significant cardiovascular diseases, including 
any of the following: 
• Ongoing or history of uncontrolled or symptomatic ischemic myocardiopathy within 6 
months prior to randomization. 
• Known left ventricular ejection fraction < 50%, left ventricular hypertrophy, ventricular 
arrhythmias, bradycardia (heart rate < 50 bpm). 
• History of myocardial infarction, or severe/unstable angina, within 6 months prior to 
randomization. 
• New York Heart Association grade ≥ 3 congestive heart failure. 
• Congenital long QT syndrome. 
• Family history of long QT syndrome. 
• Symptomatic pulmonary embolism within 6 months prior to randomization. 
• Ongoing or known history of transient ischemic attacks or stroke within 6 months prior 
to randomization. 
• QTc using Fridericia’s formula (QTcF) interval > 450 ms for males and > 470 ms for 
females. 
17. Symptomatic pulmonary disease requiring continuous or intermittent oxygen supply. 
18. History of another malignancy within the last 3 years prior to randomization, with the 
exception of completely resected non-melanoma cell skin cancer outside the head and 
neck area or completely resected stage I breast cancer, or completely resected in-situ non-
muscular invasive bladder, cervix and/or uterine carcinomas or T1a squamous cell 
carcinoma of the esophagus. 
19. Known contraindication to undergoing positron emission tomography with 2-deoxy-2-
[fluorine-18] fluoro-D-glucose (18F-FDG-PET) scans, and/or both contrast-enhanced MRI 
and contrast-enhanced CT scans. 
20. Known allergy to xevinapant, cisplatin, carboplatin, other platinum-based agent or any 
excipient known to be present in any of these products or in the placebo formulation. 
21. Non-compensated or symptomatic liver cirrhosis (Child-Pugh score: B or C). 
22. Any ongoing condition or disorder, before randomization, including drug(s) or alcohol 
abuse, which in the judgment of the Investigator would make the participant inappropriate 
for entry into the study or precluding his/her ability to comply with study procedures. 
 
5.3. 
Lifestyle Considerations  
During the study, participants are asked to refrain from consumption of grapefruit juice, grapefruit-
containing products, St John’s Wort (= Hypericum perforatum, millepertuis) and St John’s Wort-
containing products because of the risk of DDIs with P-gp resulting in a decrease in xevinapant 
exposure (see also Section 6.5.3.1). 
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5.4. 
Screen Failures  
Screen failures are participants who have signed the ICF and for whom a study-specific 
identification number has been assigned (screened participants) but who were not enrolled 
because they failed to meet the eligibility criteria or discontinued study participation during the 
screening period for other reason(s). 
In accordance with the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from Regulatory Authorities, only a minimal set of data 
are collected on screen failures, i.e., demographic data, screening failure reason(s) and any 
serious adverse event (SAE). 
Re-testing of participants in cases of physical and/or laboratory parameters abnormalities will be 
allowed within 28 days after the signature of ICF (screening period). 
Beyond the 28 days after signature of ICF, participants may be re-screened in certain 
circumstances for enrolment into the study: 
• 
A participant consented to participate, met the eligibility criteria but was delayed in starting 
due to a change in situation (e.g., family issues, request for attending a private matter, 
etc.). 
• 
A participant failed eligibility due to an acute event that resolved or was stabilized with 
medications. 
• 
Reversible causes of screening failure that were adequately treated and/or resolved. 
• 
A participant failed eligibility due to logistical/operational constraints (e.g., assessment 
could not be done in time due to logistical constraints or had to be repeated but time was 
limited, laboratory results were delayed, IMRT plan was not approved in time, etc.). 
Only one rescreening is allowed. 
In case of rescreening, the participant will be required to sign another ICF. A new electronic case 
report form (eCRF) will be used but the participant number will remain the same. The participant 
will be flagged in the eCRF as having been re-screened. All assessments should be repeated 
according to instructions provided for the initial screening (see Section 1.3 and Table 1-1). As with 
initial screening procedures, 18F-FDG-PET, i.v. contrast-enhanced CT-scan or MRI of head and 
neck, and CT-scan of chest are only accepted if they are performed within 4 weeks before 
randomization. Dental examination, audiometry, HBV/HCV/HIV tests, and fiberoptic endoscopy 
performed within 2 weeks before the last signed ICF do not have to be repeated during screening. 
 
5.5. 
Strategies for Recruitment and Retention  
The target sample size is 700 eligible participants worldwide enrolled from approximately 
280 recruiting sites. The following geographic areas are expected to participate: North America, 
Latin America, Europe, Middle East, and Asia Pacific. Assuming a 30% screen failure rate, 
approximately 1000 participants will be screened in order to achieve the target number of eligible 
participants.  
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Note: Additional Chinese participants from China Mainland will be randomized in a China-specific 
extension cohort (see Section 13.9 for further details). 
Eligible participants will be randomized in a 1:1 ratio to receive xevinapant + CRT (Arm A) or 
matched placebo + CRT (Arm B). The annual lost to follow-up/dropout rate is expected to be 5% 
in both arms. 
Stratification factors are presented in Section 6.3. 
Participants will be recruited from participating investigational sites either by a direct approach 
from the physician or Health Care Professional or following an enquiry from a referring site or 
participant. Other measures will be implemented to reach out to potential participants which will 
include a study-specific website for participants, engagement of Patient Advocacy Groups and 
selected media coverage, when allowed by local legislation. 
Materials focused on participant recruitment and retention will follow local regulations and may 
include, among others: study posters, participant brochure, patient participation and appointment 
card, participant’s diary and welcome guide. 
To assist Health Care Professionals with participant identification a range of materials will also be 
used such as: Health Care Professionals Brochure, Health Care Professionals Referral Form, 
Eligibility Checklist, Inclusion/Exclusion card, Health Care Professional study website. 
Participants will not be compensated for participation in this study, but travel costs may be 
reimbursed, when allowed by local regulations. The service of monitoring and managing the 
participant travel and reimbursement costs will be provided by the study Contract Research 
Organization (CRO). 
6. STUDY INTERVENTION  
6.1. 
Study Intervention Administration  
6.1.1. 
Study Intervention Description  
Study intervention or study treatment includes blinded administration of investigational treatments 
(xevinapant, matched placebo, cisplatin and carboplatin) and background treatments. 
The investigational treatment is defined as a pharmaceutical form of an active substance or 
placebo being tested or used as a reference in a clinical study, including products already with a 
marketing authorization but used or assembled (formulated or packaged) differently than the 
authorized form, or used for an unauthorized indication, or when used to gain further information 
about the authorized form. In the current protocol, xevinapant, matched placebo, cisplatin and 
carboplatin are investigational treatments. 
Background treatments are medicinal products administered to each of the clinical study 
participants, regardless of randomization group, to treat the indication which is the object of the 
study. In the current protocol, IMRT is considered as background treatment. 
The following investigational and background treatments will be administered during the study 
according to randomization (see Section 6.1.2 for dosing and administration details): 
• 
Arm A: 3 cycles of xevinapant (200 mg/day from Day 1 to 14, per cycle) + IMRT (70 Gy in 
35 fractions over 7 weeks, 2.0 Gy/fraction, 5 days/week + high-dose cisplatin (100 mg/m2 
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on Day 2, per cycle), followed by 3 cycles of monotherapy of xevinapant (200 mg/day from 
Day 1 to 14, per cycle). 
or 
• 
Arm B: 3 cycles of placebo (from Day 1 to 14 per cycle) + IMRT (70 Gy in 35 fractions 
over 7 weeks, 2.0 Gy/fraction, 5 days/week) + high-dose cisplatin (100mg/m2 on Day 2, 
per cycle), followed by 3 cycles of monotherapy of placebo (from Day 1 to 14, per cycle). 
One cycle is composed of 3 weeks. 
The administration schedule of xevinapant/placebo, chemotherapy and IMRT is presented in 
Table 1-1 and Table 1-2. 
 
6.1.2. 
Dosing and Administration  
6.1.2.1. 
Xevinapant or Matched Placebo  
Xevinapant oral solution at 200 mg/day or matched placebo will be administered once daily from 
Day 1 to Day 14 of a 3-week cycle, during 6 cycles (see Table 1-2). 
Xevinapant/matched placebo should be administered orally, early in the morning (except on days 
 where a specific procedure described below applies), on an empty stomach (no 
food intake within 2 hours before xevinapant/matched placebo administration). Participants should 
fast for at least 1 hour after dosing. Water is permitted freely before and after xevinapant/matched 
placebo intake. If necessary, the oral solution will be administered via a nasogastric tube, 
percutaneous endoscopic gastrostomy, or percutaneous endoscopic jejunostomy tube. 
If the participant forgets to take the scheduled dose of xevinapant/matched placebo more than 8 
hours after the time of intake, then the participant should skip that dose. 
Xevinapant/matched placebo will be dispensed by the medical staff or Pharmacist of the 
investigational sites. The participant will receive xevinapant or the matched placebo on an 
outpatient basis. 
On days 
 at C1D2, C1D8, C2D2, C3D1, and C3D2, participants should take their 
doses at the hospital, where the administration of xevinapant or the matched placebo will be 
supervised and recorded by the medical staff 
 
 The time of dose administration and the time of 
blood draw should be recorded in the eCRF and in the participant’s diary. In addition, on C1D7, 
the time of the dose taken at home needs to be recorded in both the eCRF and the participant’s 
diary. On days 
, at C3D8 and C4D1, xevinapant/placebo is taken, and the time of 
dosing (C3D8 and C4D1) must be recorded both in the eCRF and the participant’s diary. On 
C3D15, the last xevinapant/placebo dose timing (taken at home on C3D14) must be recorded 
both in the eCRF and the participant’s diary. 
The treatment schedule of xevinapant or the matched placebo is presented in Table 1-1 and 
Table 1-2. Participants will be instructed by the medical staff on how to self-administer xevinapant 
or the matched placebo at home. The participant should inform the medical staff of any missed or 
delayed doses. In addition, a Participant Diary will be provided to participants to record 
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x e vi n a p a nt/ m at c h e d pl a c e b o i nt a k e s at h o m e. Pl e a s e r ef er t o S e cti o n s 6. 4  a n d 8. 3. 8  f or f urt h er 
d et ail s.  
6. 1. 2. 1. 1.  
C o n c u rr e nt A d mi ni str ati o n t o C h e m ot h er a p y a n d I M R T  
O n d a y s w h e n I M R T a n d c h e m ot h er a p y ar e t o b e a d mi ni st er e d ( s e e T a bl e  1 -2 ), 
 
 
 c h e m ot h er a p y s h o ul d b e a d mi ni st er e d 
pr ef er a bl y b ef or e I M R T.  
O n d a y s w h e n I M R T i s t o b e a d mi ni st er e d wit h o ut c h e m ot h er a p y ( s e e T a bl e  1 -2  a n d S e cti o n 
6. 1. 2. 3 ), x e vi n a p a nt or m at c h e d pl a c e b o s h o ul d b e pr ef er a bl y a d mi ni st er e d b ef or e I M R T. 
If c h e m ot h er a p y or I M R T ar e p ut o n h ol d or di s c o nti n u e d, pl e a s e r ef er t o S e cti o n 6. 1. 2. 1. 2  t o a d a pt 
x e vi n a p a nt a d mi ni str ati o n a c c or di n gl y.  
6. 1. 2. 1. 2.  
D o s e M o difi c ati o n, I nt err u pti o n a n d Di s c o nti n u ati o n of 
X e vi n a p a nt/  M at c h e d Pl a c e b o Tr e at m e nt   
F or p arti ci p a nt s w h o d o n ot t ol er at e t h e st u d y tr e at m e nt, a dj u st m e nt s t o t h e st u d y tr e at m e nt ar e 
p er mitt e d t o all o w t h e p arti ci p a nt  t o c o nti n u e o n-st u d y tr e at m e nt.  
T h e g ui d eli n e s f or x e vi n a p a nt/ m at c h e d pl a c e b o d o s e m o difi c ati o n s f or t o xi citi e s c o n si d er e d at 
l e a st p o s si bl y r el at e d t o st u d y tr e at m e nt ar e o utli n e d i n T a bl e  6 -1  a n d T a bl e  6 -2  , f or c o m bi n ati o n 
t h er a p y a n d m o n ot h er a p y, r e s p e cti v el y. T h e s e d o s e m o difi c ati o n s ar e r e c o m m e n d ati o n s u nl e s s 
ot h er wi s e s p e cifi e d a s m a n d at or y. All d o s e m o difi c ati o n s s h o ul d b e b a s e d o n t h e w or st pr e c e di n g 
t o xi cit y ( N CI-C T C A E v 5. 0). A d diti o n all y, n o n -tr e at m e nt-r el at e d e v e nt s or u n e x p e ct e d t o xi citi e s 
m a y r e q uir e i nt err u pti o n of s t u d y tr e at m e nt at t h e di s cr eti o n of t h e I n v e sti g at or. 
F or e a c h p arti ci p a nt , a m a xi m u m of 2 d o s e r e d u cti o n s of x e vi n a p a nt/ m at c h e d pl a c e b o will b e 
all o w e d d uri n g t h e st u d y.  
T h e v ol u m e of t h e or al s ol uti o n e q ui v al e nt t o e a c h d o s e l e v el i s t h e f oll o wi n g:  
•  
Pl a n n e d d o s e (l e v el 0):  
 c orr e s p o n d s t o 2 0 0 m g/ d a y of x e vi n a p a nt 
•  
D o s e l e v el -1:   
 
 c orr e s p o n d s t o 1 5 0 m g/ d a y of x e vi n a p a nt 
•  
D o s e l e v el -2:   
 
 c orr e s p o n d s t o 1 0 0 m g/ d a y of x e vi n a p a nt 
G e n er al r ul e s f or x e vi n a p a nt/ m at c h e d pl a c e b o a d mi ni str ati o n t hr o u g h o ut t h e tr e at m e nt p eri o d ( C 1 
t o C 6) ar e: 
•  
T h e n u m b er of tr e at m e nt d a y s wit h x e vi n a p a nt  i nt a k e s h o ul d n ot e x c e e d 1 4 d a y s p er c y cl e. 
•  
I n c a s e of t ol er a bilit y i s s u e s, u p t o 2 s e q u e nti al x e vi n a p a nt  d o s e r e d u cti o n s  of  
 
( 
of or al s ol uti o n) p er st e p will b e all o w e d, d o w n t o a mi ni m u m d o s e of  
 
 of or al s ol uti o n). If f urt h er d o s e r e d u cti o n i s r e q uir e d, t h e p arti ci p a nt  m u st b e 
p er m a n e ntl y di s c o nti n u e d fr o m x e vi n a p a nt / m at c h e d pl a c e b o a d mi ni str ati o n ( ot h er o n g oi n g 
tr e at m e nt s c a n c o nti n u e, s e e S e cti o n s 6. 1. 2. 2  a n d 6. 1. 2. 3 ). 
•  
If t h e o n s et of s e v er al t o xi citi e s l e a d s t o c o nfli cti n g r e c o m m e n d ati o n s a s d e s cri b e d i n 
T a bl e  6 -1  t h e m o st c o n s er v ati v e d o s e a dj u st m e nt a m o n g all t o xi citi e s pr e s e nt e d m u st b e 
f oll o w e d. 
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• 
No re-escalation of xevinapant/matched placebo dose after dose reduction will be allowed 
during the study. Once xevinapant or matched placebo dose has been reduced, participant 
will keep receiving the same dose until the EOT, or until further dose reduction or 
permanent treatment discontinuation, if required due to tolerability issues. 
• 
Xevinapant doses/matched placebo that were omitted on a specific day should NOT under 
any circumstances be administered any other day in addition to the scheduled intake. 
• 
No additional dose should be re administered after vomiting; the participant must wait for 
the next scheduled intake. 
• 
If during the monotherapy part of the treatment, a participant requires a 
xevinapant/matched placebo dose interruption of more than 21 consecutive days due to 
study treatment-related toxicities, the Investigator should consider discontinuing the 
treatment. If a participant is discontinued from the monotherapy treatment, the EOT visit 
should be performed. 
• 
Chemotherapy discontinuation will NOT result in xevinapant/matched placebo 
discontinuation. 
• 
During the combination treatment period, if IMRT is interrupted, xevinapant/matched 
placebo should be interrupted. If IMRT is restarted, xevinapant/matched placebo should 
be resumed at the next originally scheduled intake day of xevinapant/matched placebo, 
provided other rules of dose interruption are not met (see Section 6.1.2.3). If IMRT is 
permanently discontinued due to safety issues, then xevinapant/matched placebo 
administration should be maintained, and the participant can enter the monotherapy period. 
Otherwise, xevinapant/matched placebo treatment should be discontinued permanently, 
the EOT visit should be performed, and the participant should stay on study for follow-up 
as per protocol. IMRT may be interrupted for up to a maximum of 10 treatment days in 
total. 
• 
Participants who prematurely discontinue from all treatments, i.e., chemotherapy, IMRT 
and xevinapant/matched placebo, in the absence of an EFS event will undergo the EOT 
visit and then enter the EFS follow-up period according to schedule. 
Any dose modification and dose interruption including the reason must be recorded on the Dosage 
Administration Record eCRF. 
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6.1.2.1.3. 
End of Xevinapant/Matched Placebo Treatment  
Xevinapant/matched placebo treatment will be administered until the 6 cycles of therapy (i.e., 3 
cycles of combination therapy followed by 3 cycles of monotherapy) are completed or until any of 
the study intervention discontinuation criteria described in Section 7.1 occur. 
Note: If IMRT is permanently discontinued due to severe or intolerable toxicities as per 
Investigator’s discretion, then the participant can enter the monotherapy period. 
Discontinuation from study treatment does not mean discontinuation from the study. Procedures 
to be followed in the event of a study treatment discontinuation are presented in Section 7.1. 
Procedures for discontinuation from study (not only study treatment) are described in Section 7.3. 
 
6.1.2.2. 
Chemotherapy  
All participants will receive high-dose cisplatin (100 mg/m2) intravenously over at least 90 minutes 
on Day 2 Q3W up to a maximum of 3 cycles in total (see administration schedule in Table 1-1 and 
Table 1-2). If body surface area is >2.00 m2, total administered dose will be capped at a maximum 
of 200 mg. Please consult and follow cisplatin administration instructions provided in your local 
label. The infusion has to be administered with pre- and post-infusion hydration +/- mannitol and/or 
diuretics, according to institutional guidelines. Any pre-existing dehydration should be corrected. 
Please refer to Appendices 13.2 and 13.3 for additional information on cisplatin administration and 
suggested hydration regimen. 
 
 
eGFR (using the CKD-EPI creatinine formula) should be ≥60 mL/min/1.73m2 before administration 
of cisplatin at C1D2; re-treatment conditions as specified in Table 6-1 should be met. 
Participants should receive at least one dose of cisplatin on C1D2. 
Standard antiemetic prophylaxis for high-dose cisplatin containing regimens are mandatory 
starting on Day 1 of each chemotherapy containing cycle. Standard antiemetics guidelines 
(administration of pre- and post-treatment 5-HT3 receptor antagonists, neurokinin-1 receptor 
antagonists and dexamethasone [or any other corticosteroid at equivalent dose i.v.] according to 
the 2016 MASCC and ESMO guideline (Roila et al. 2016)]) are provided in Section 6.5.1; however 
the specifics of the regimen are at the discretion of the treating physician, provided adequate 
control is achieved. 
Note:  Dose and schedule of dexamethasone coupled with its wide availability in various forms 
established it as the agent of choice in the 2016 MASCC and ESMO guideline. If an equivalent 
dose of corticosteroids is used according to institutional guidelines, the risk of increased toxicity 
to corticosteroids should be carefully monitored. Elevations of plasma levels may be triggered by 
xevinapant inhibition of CYP3A4.  
The participant can switch to carboplatin in C2 and/or C3 as per the dose modifications outlined 
in Table 6-1 (NCCN Chemotherapy Order Templates 2020). Please consult and follow the 
carboplatin administration instructions provided in your local label. 
No pre- or post-treatment hydration or forced diuresis is required for carboplatin administration. 
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6.1.2.2.1. 
Dose Modification, Interruption and Discontinuation of 
Chemotherapy  
Permitted cisplatin dose levels: 
• 
Planned dose (level 0): corresponds to cisplatin 100 mg/m2 
• 
Dose level -1: corresponds to cisplatin 75 mg/m2 (-25% from prior dose level: capped at 
150 mg total dose) 
• 
Dose level -2: corresponds to cisplatin 50 mg/m2 (-25% from prior dose level: capped at 
100 mg total dose) 
For participants switching to carboplatin: carboplatin AUC = 5 mg·min/mL or AUC = 4 mg·min/mL 
is allowed. 
Please refer to Table 6-1 for instructions on dose modifications, interruption, and discontinuation 
of chemotherapy in case of toxicity suspected to be related to study treatment. 
Toxicity related to chemotherapy administration includes but is not limited to nausea, vomiting, 
renal toxicity (with an elevation of blood urea nitrogen and creatinine and impairment of 
endogenous creatinine clearance, as well as renal tubular damage, which appears to be transient), 
peripheral neuropathy, ototoxicity (with hearing loss that initially is in the high-frequency range, as 
well as tinnitus) and hyperuricemia. Much more severe and prolonged toxicity has been observed 
in participants with abnormal or obstructed urinary excretory tracts. Myelosuppression, often with 
delayed anemia is expected. 
Chemotherapy dose adjustments at the start of a cycle should be based on the nadir of 
hematologic counts or maximum non-hematologic toxicity from the previous treatment cycle. 
chemotherapy infusion may be delayed to allow for sufficient recovery time. 
 
6.1.2.2.2. 
End of Chemotherapy  
Chemotherapy will be administered until completion of the 3 cycles of platinum-based therapy 
planned in the study or until any of the study intervention discontinuation criteria described in 
Section 7.1 occur. 
Note: Chemotherapy discontinuation will not result in xevinapant/matched placebo discontinuation 
or study treatment discontinuation. 
Dose modifications, interruption, including switching from cisplatin to carboplatin, and permanent 
discontinuation of any of the components of the study intervention is to be recorded in the Dosing 
Case Report Form (CRF) of each component of the study intervention. For each action, the reason 
must be recorded. 
Discontinuation from study treatment does not mean discontinuation from the study. Procedures 
to be followed in the event of a study treatment discontinuation are presented in Section 7.1. 
Procedures for discontinuation from study (not only study treatment) are described in Section 7.3. 
 
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6.1.2.3. 
Radiotherapy  
Standard fractionation IMRT (as fully described in the IMRT manual) is to be started on C1D1 after 
administration of xevinapant/matched placebo (see administration schedule in Table 1-1 and 
Table 1-2). On days where all treatment components should be administered, IMRT should be 
preferably administered after xevinapant/matched placebo and chemotherapy. 
IMRT will be delivered per Table 6-3 and the following: 
• 
To the PTV and high-risk clinical target volume: 70 Gy in 35 fractions over 7 weeks, 
2.0 Gy/fraction, 5 days/week. Missed treatments due to holidays or logistic reasons can 
be compensated by delivering the missed fraction before or after the end of the 
combination treatment period (i.e., up to Week 9 after administration of first dose) (see 
Section 6.1.2.3.1). 
• 
Elective irradiation (low-risk) to locoregional areas, 56 Gy (1.6 Gy/fraction per day, 
5 fractions per week [5/7 days]). 
 
Table 6-3 Radiation therapy scheme  
 
Total dose in Gy 
Dose in Gy 
Number of days 
 
PTV 70 
70 
2 
35 
5 fractions per week over 7 weeks 
PTV 56 
56 
1.6 
35 
5 fractions per week over 7 weeks 
Abbreviations: PTV: Planning target volume. 
 
The RT-QA Review Center (Section 11.2.2) will centrally review the IMRT treatment plan(s) to 
ensure compliance with protocol guidelines and provide feedback to the site. 
The IMRT treatment plan for each participant must be submitted electronically to the RT-QA 
Review Center as soon as possible and no later than 5 business days prior to the start of IMRT. 
The digital data must include treatment planning of CT-scan, structure, plan, and dose files (please 
refer to the RT-QA Manual/Guide). The RT-QA Review Center will evaluate IMRT delivery and any 
critical/major deviations from the submitted plan during study treatment period. RT-QA Review 
Center approval of the IMRT plan is requested before starting the first fraction administration. 
 
6.1.2.3.1. 
Treatment Interruption  
IMRT interruption is strongly discouraged; any interruption must be clearly indicated in the 
treatment record and reasons should be documented. 
IMRT may be interrupted for up to a maximum of 10 treatment days in total to allow 
resolution/improvement of radio-chemo toxicities such as grade 4 mucositis measured by physical 
or functional examination, or grade 4 radiodermatitis (see section 6.1.2.3.2 for management of 
those toxicities). 
Treatment interruption due to a non-medical reason should be minimized as much as possible 
and should not exceed 2 consecutive treatment days per interruption (Radiologists 2020). In case 
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of interruption for technical reasons (e.g., malfunction or revision of the treatment machine), 
continued treatment must be ensured, and the use of another unit is recommended. For units that 
have different energy levels, it is recommended to perform the dosimetry on an alternative device. 
If a fraction has to be compensated, it can be administered after the planned 35 fractionation 
days (cycle 1 to 3) or it can be compensated during the 35 fractionation days. If compensated 
during the 35 fractionation days, the fractions should be at least 6 hours apart. Xevinapant / 
placebo administration should not be compensated. In any case, there must be no more than 
5 days of treatment in a given week.  
If IMRT is permanently discontinued due to severe and intolerable toxicities as per Investigator’s 
judgment, then xevinapant/matched placebo monotherapy administration should be maintained, 
and the participant can enter the monotherapy period. 
 
6.1.2.3.2. 
Management of Acute “in Radiation Field” Toxicity  
If dermatitis, mucositis, or dysphagia occurs, the possibility of IMRT interruption should be 
assessed according to their severity. Institutional guidelines on prophylaxis and dental hygiene 
will be followed for management of skin and mucosal toxicity. 
For any other degree of minor toxicity, the necessary support measures must be taken to ensure 
treatment continuity (Peterson et al. 2015). 
In the event of mucositis, the following recommendations will be considered: 
• 
Rapid escalation of analgesics using the World Health Organization cancer pain relief 
ladder (WHO 2018). 
• 
Enteral or parenteral nutritional support according to the institutional guideline. Enteral 
nutritional support is strongly recommended if weight loss is ≥ 5%. If the weight loss is ≥ 
10%, the use of a nasogastric or gastrostomy tube must be implemented as quickly as 
possible (Elad 2019). 
The management of radiation dermatitis should be based on the severity of symptoms, as 
determined by Radiation Therapy Oncology Group and should follow the recommendations by the 
Supportive Care Guidelines Group. 
 
6.1.2.3.3. 
End of Radiotherapy  
Radiotherapy will be administered until completion of the IMRT dose and schedule (see Table 6-3) 
planned in the study or until any of the study intervention discontinuation criteria described in 
Section 7.1 occur. 
Discontinuation from study treatment does not mean discontinuation from the study. Procedures 
to be followed in the event of a study treatment discontinuation are presented in Section 7.1. 
Procedures for discontinuation from study (not only study treatment) are described in Section 7.3. 
 
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6.2. 
Preparation/Handling/Storage/Accountability  
6.2.1. 
Acquisition and Accountability  
The investigational treatments (xevinapant/matched placebo, cisplatin, and carboplatin; see 
Section 6.1) will be provided to the Investigators by and under the responsibility of the Sponsor, 
who will also ensure release of the investigational treatments as per current Good Manufacturing 
Practice (GMP) guidelines. Any documentation required by local Health Authorities for import of 
the investigational treatments will be appropriately submitted. 
The Investigator, Pharmacist or other authorized personnel at each study site will inventory and 
acknowledge receipt of all shipments of investigational treatments. The investigational treatments 
accompanied by analytical reports when appropriate, must be kept in a locked area with access 
restricted to designated study personnel. 
Investigational treatment acquisition, dispensing, accountability and reconciliation will be 
managed through an Interactive Web Response System (IWRS). 
The Investigator/Pharmacist at each study site will keep accurate records of the investigational 
treatment (and other study-related drugs) dispensed. Specific procedures for investigational 
treatment preparation, handling, storage, and accountability will be detailed in the Pharmacy 
Manual, provided by the Sponsor to each study site. 
During the study, whenever appropriate, partially used and unused investigational treatments will 
be counted and returned in the original packaging to the Sponsor or destroyed with Sponsor 
written permission. The Sponsor’s monitor/representative will review drug accountability records 
and ensure investigational treatment return to depot for destruction if not destroyed on site. 
Any discrepancies between the investigational treatments returned and the expected balance 
must be documented. 
Unused investigational treatments must not be discarded or used outside of the frame of the 
present study. 
When the above tasks are delegated to a Pharmacist, the Investigator remains ultimately 
responsible for the maintenance of accurate drug dispensing records. 
 
6.2.2. 
Formulation, Appearance, Packaging, and Labeling  
Packaging and labeling will be in accordance with applicable local regulatory requirements and 
applicable GMP guidelines. 
 
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6. 2. 2. 1.  
F or m ul ati o n, A p p e ar a n c e, P a c k a gi n g   
T a bl e  6 -4  F or m ul ati o n, a p p e ar a n c e a n d p a c k a gi n g of i n v e sti g ati o n al tr e at m e nt s: x e vi n a p a nt a n d 
pl ati n u m -b a s e d c h e m ot h er a p y   
Pr o d u ct  
P ot e n c y  
A p p e ar a n c e  
Pa c k a gi n g  
X evi n a p a nt a 
or Pl ac e b o a 
m g/ m L  
N ot 
a p plic a bl e  
Or al s ol uti o n  
 
 
Cis pl ati n  
 
1 m g/ m L  
 
C o nc e ntr at e f or s ol uti o n 
f or i nf usi o n 
 
Pack a g e c o nt ai ns 1 vi al ( 5 0 m L) of cis pl ati n c o nc e ntr at e f or s ol uti o n f or 
i nf usi o n. 
Eac h p ack a g e is l a b el e d as a p pr o pri at e t o c o m ply wit h l oc al 
r e g ul ati o ns. 
 
C ar b o pl ati n  
1 0 m g/ m L  C o nc e ntr at e f or s ol uti o n 
f or i nf usi o n 
Pack a g e c o nt ai ns 1 vi al ( 1 5 m L or 6 0 m L) of c ar b o pl ati n c o nc e ntr at e 
f or s ol uti o n f or i nf usi o n. 
Eac h p ack a g e is l a b el e d as a p pr o pri at e t o c o m ply wit h l oc al 
r e g ul ati o ns. 
 
a   
T h e f or m ul ati o n will b e s p e cifi e d i n t h e P h ar m a c y M a n u al.  
6. 2. 2. 2.  
L a b eli n g   
M e di c ati o n l a b el s will c o m pl y wit h t h e l e g al r e q uir e m e nt s of e a c h c o u ntr y a n d will b e pri nt e d i n t h e 
l o c al l a n g u a g e. T h e st or a g e c o n diti o n s f or t h e i n v e sti g ati o n al tr e at m e nt s will b e d e s cri b e d o n t h e 
m e di c ati o n l a b el.  
 
6. 2. 3.  
Pr o d u ct St or a g e a n d St a bilit y   
X e vi n a p a nt or al s ol uti o n or pl a c e b o s h o ul d b e st or e d u n d er c o ntr oll e d t e m p er a t ur e at 2° C t o 8° C 
( 3 6° F t o 4 6° F). D o n ot fr e e z e. K e e p m e di c ati o n i n it s ori gi n al c o nt ai n er. 
Ci s pl ati n a n d c ar b o pl ati n s h o ul d b e st or e d a c c or di n g t o t h e dr u g l a b el.  
A n y a d diti o n al st or a g e r e q uir e m e nt s will b e f urt h er d et ail e d i n t h e P h ar m a c y M a n u al pr o vi d e d b y 
t h e S p o n s or t o e a c h st u d y sit e. 
 
6. 2. 4.  
Pr e p ar ati o n   
F or or al ( p. o.) a d mi ni str ati o n  of 2 0 0 m g of x e vi n a p a nt or al s ol uti o n or pl a c e b o: or al i nt a k e b y t h e 
p arti ci p a nt  dir e ctl y fr o m t h e 
 
F or e nt er al a d mi ni str ati o n  of 2 0 0 m g of x e vi n a p a nt or al s ol uti o n or pl a c e b o: wit h dr a w al of t h e 
r e q uir e d v ol u m e b y t h e p arti ci p a nt  u si n g a 5 m L s yri n g e. N ot e: 
 t h e u s e 
of l ar g er s yri n g e s i s n ot f e a si bl e.  
I n c a s e of d o se r e d u cti o n , p. o. a n d e nt er al a d mi ni str ati o n of 1 5 0 m g/ 7. 5  ml or 1 0 0  m g/ 5  ml (f or 
x e vi n a p a nt) or pl a c e b o: wit h dr a w al of t h e r e q uir e d v ol u m e b y t h e p arti ci p a nt  u si n g a 5  ml s yri n g e. 
N ot e: 
, t h e u s e of l ar g er s yri n g e s i s n ot f e a sibl e.  
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6.3. 
Measures to Minimize Bias: Randomization and Blinding  
To ensure that treatment assignment is unbiased and concealed from participants and Investigator 
staff, randomization will be performed using the following procedure. 
All participants will be centrally assigned to randomized study intervention using an IWRS. A web 
address and a manual for the IWRS will be provided to each site. The Investigator or authorized 
person will be responsible for activating the IWRS. 
During screening or at C1D1 and upon confirmation of eligibility, the participant will be randomized 
to one of the 2 study arms in a 1:1 ratio. Each medication kit will be identified by a unique 
medication number. To avoid unintentional unblinding, those numbers will be assigned following 
a randomized sequence. At the D1 visit of each cycle, the IWRS will assign 2 kit numbers per 
participant. 
Eligible participants will be randomized in a 1:1 ratio to receive xevinapant + CRT (Arm A) or 
matched placebo + CRT (Arm B). The following stratification factors will be considered for the 
randomization: 
• 
Region: North America vs Western Europe vs Rest of the World. 
• 
Primary tumor site: larynx vs other. 
• 
Lymph node involvement: N0-1 vs N2 vs N3. 
• 
T size: T4 vs other. 
The randomization mechanism will have 2 stages: 
• 
First stage: randomization will be either to “balanced part” (with probability 0.2) or “adaptive 
part” (with probability 0.8). 
• 
Second stage: randomization will be based on the result of the first stage. If randomization 
from the first stage is: 
o to the “balanced part”: treatment assignment will be in a 1:1 ratio to either 
xevinapant + CRT (Arm A) or matched placebo + CRT (Arm B), regardless of the 
stratification factors. 
o to the “adaptive part”: a dynamic allocation will be carried out following the 
methodology proposed by Pocock et al. (Pocock et al. 1975; Lebowitsch et al. 
2012). An Overall Imbalance Score (OIS, using the range measure) will be 
calculated based on levels of individual stratification factors of participants both for 
the scenario when xevinapant + CRT will be assigned and scenario when placebo 
will be assigned. Based on the values of OIS for each arm, probabilities for 
assignment will be derived: 
▪ 
If OIS is the same for both arms, then the randomization will be 1:1 to either 
xevinapant + CRT or placebo + CRT. 
▪ 
If OIS is different between the 2 arms, then assignment to the treatment 
leading to the highest OIS will have a probability of 0.2 and assignment to 
treatment leading to lower OIS will have a (complementary) probability of 
0.8. 
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This two-stage process was introduced to add a random factor to the treatment allocation while 
minimizing the imbalance between treatments and preventing perfectly deterministic allocation 
and allocation concealment. 
The 1st xevinapant/matched placebo administration should be performed within 1 week maximum 
following randomization. 
If the participant fails to be randomized, the screening failure reason should be recorded in the 
eCRF (see also Section 5.4). 
In the event a participant is randomized but does not begin treatment, that participant’s 
randomization number will not be reassigned. 
Randomization codes will be kept confidential and maintained blinded to the Investigators/site 
personnel, CRO and Sponsor team until the database is locked for primary analysis. However, 
randomization codes will be disclosed to the third party laboratory in charge of bioanalytical assays 
 to prevent analyses of placebo participants’ samples while allowing 
samples analysis within the samples stability period. Furthermore, the IDMC and supporting 
independent statistical data center will be unblinded to treatment especially for the interim 
analysis. The IDMC will first share recommendation(s) based on the results of the interim efficacy 
analyses to the Firewall Team and jointly discuss results, as needed, for final Sponsor decision 
according to the protocol, keeping all individuals involved in the study conduct blinded to preserve 
its integrity. 
 
Emergency unblinding 
In case of an emergency, the Investigator has the sole responsibility for determining if unblinding 
of a participants’ intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. Only medical reasons should trigger an emergency 
unblinding. 
The Investigator will be able to break the blind through the IWRS system without prior approval 
from the Sponsor. The IWRS will be programmed with blind-breaking instructions and will 
automatically notify the Sponsor in case of unblinding. 
The date and reason of blind break must be recorded in the source documentation and CRF. The 
Investigator will inform the participant how to contact his/her backup in cases of emergency when 
he/she is unavailable. 
Xevinapant/matched placebo must be discontinued after emergency unblinding. 
6.4. 
Study Intervention Compliance  
Participants’ compliance to each component of the study intervention (i.e., xevinapant/matched 
placebo, chemotherapy and IMRT) will be verified by direct visual supervision by the Investigator 
or his/her designee when administered at the hospital. 
When xevinapant/matched placebo administration is taken at home, compliance will be monitored 
via a participant dosing diary (see Section 8.3.8) to be filled out after each intake. Participants will 
be instructed to return used and unused xevinapant or the matched placebo vials to the site to 
allow drug accountability by the medical staff. 
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Compliance will be assessed by the timepoint/schedule, sequence of administration, number of 
cycles, dose intensity, volume/amount administered and duration of administration. 
For each component of the study intervention (i.e., xevinapant/matched placebo, chemotherapy 
and IMRT) the reasons for dose modification, interruption and discontinuation must be recorded 
in the CRF. 
 
6.5. 
Prior, Concomitant, and Subsequent Therapy  
Any medication or therapy received after the ICF signature and prior to the first dose of study 
treatment, whether or not such medication/therapy is continued at the time of starting study 
treatment, is considered as prior therapy. 
Any therapy started between the first dose of study intervention and the EOT is considered 
concomitant therapy. 
Any antineoplastic therapies (e.g., medication, surgery, any further RT) started between the EOT 
and the EOS are considered subsequent therapies. 
All prior, concomitant and subsequent antineoplastic therapy (medication or procedures) must be 
recorded in the Prior, Concomitant, and Subsequent antineoplastic medication eCRF. Further 
instructions will be provided in the eCRF completion guidelines. 
 
6.5.1. 
Permitted Concomitant Medications  
6.5.1.1. 
Antiemetics  
The specific antiemetic regimen is at the discretion of the Investigator, provided adequate control 
is achieved. Related information should be reported in the eCRF. For participant receiving 
cisplatin, antiemetic therapy including dexamethasone (or any other corticosteroid at equivalent 
dose i.v.), 5-HT3 serotonin receptor antagonists and neurokinin-1 receptor antagonists can be 
administered as per 2016 MASCC and ESMO guideline (Roila et al. 2016). 
For instance, the Investigator can consider the following regimen: 
Day of cisplatin administration (Day 1 of cisplatin = Day 2 of each treatment cycle): 
• 
5-HT3 serotonin receptor antagonists i.v., at the appropriate antiemetic dose for highly 
emetogenic regimens. If ondansetron is used with xevinapant/matched placebo, 
participant should be monitored closely (see also Section 6.5.2). 
• 
Dexamethasone: 12 mg or any other corticosteroid at an equivalent dose orally (to be taken 
30 minutes prior to chemotherapy). 
• 
Aprepitant: oral 125 mg at least 30 minutes prior to infusion. 
Day 2-3 after cisplatin administration: Dexamethasone 8 mg + aprepitant 80 mg/day ± 5-HT3 
serotonin receptor antagonist 
Day 4 after cisplatin administration: Dexamethasone 8 mg 
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F or p arti ci p a nt s r e c ei vi n g c ar b o pl ati n, a nti e m eti c t h er a p y i n cl u di n g d e x a m et h a s o n e ( or a n y ot h er 
c orti c o st er oi d  at a n e q ui v al e nt d o s e i. v.)  a n d 5 -H T 3  s er ot o ni n r e c e pt or a nt a g o ni st s m a y b e 
a d mi ni st er e d a s p er 2 0 1 6 M A S C C a n d E S M O g ui d eli n e (R oil a  et al. 2 0 1 6 ). 
N ot e : D o s e a n d s c h e d ule of d e x a m et h a s o n e c o u pl e d wit h it s wi d e a v ail a bilit y i n v ari o u s f or m s 
e st a bli s h e d it a s t h e a g e nt of c h oi c e i n t h e 2 0 1 6 M A S C C a n d E S M O g ui d eli n e s. If a n e q ui v al e nt 
d o s e of c orti c o st er oi d s i s u s e d a c c or di n g t o i n stit uti o n al g ui d eli n e s, t h e ri s k of i n cr e a s e d t o xi cit y 
t o c orti c o st er oi d s s h o ul d b e c ar ef ull y m o nit or e d. El e v ati o n s of pl a s m a l e v el s m a y b e tri g g er e d b y 
x e vi a n a p a nt i n hi biti o n of C Y P 3 A 4.  
6. 5. 1. 2.  
S A R S -C o V -2 V a c ci n ati o n   
I n c a s e a p a rti ci p a nt i s t o b e v a c ci n at e d f or S A R S-C o V -2 d uri n g t h e st u d y  tr e at m e nt p eri o d, t h e 
f oll o wi n g a cti o n s s h o ul d b e c o n si d er e d: 
•  
A d mi ni st er o nl y a p pr o v e d v a c ci n e s.  
•  
C o n si d er c h o o si n g a n a p pr o pri at e t y p e of S A R S -C o V -2 v a c ci n e f or t h e p arti ci p a nt a n d 
c o n s ult wit h a n i nf e cti o u s di s e a s e e x p ert if d e sir e d.  
•  
N o n -r e pli c ati n g vir al v e ct or-b a s e d v a c ci n e s a n d m R N A -b a s e d v a c ci n e s ar e n ot c o n si d er e d 
li v e-att e n u at e d v a c ci n e s ( e x cl u si o n  crit eri o n # 9) a n d c a n b e a d mi ni st er e d d uri n g t h e st u d y.  
•  
If p o s si bl e, c h o o s e t h e ri g ht ti m e f or t h e v a c ci n ati o n a v oi di n g a d mi ni st eri n g t h e d o s e of 
S A R S -C o V -2 v a c ci n e d uri n g t h e l e u k o c yt e s n a dir p eri o d s d u e t o t h e c h e m ot h er a p y.  
•  
R e p ort all S A R S -C o V -2 v a c ci n e n a m e, a n d if a v ail a bl e, t h e b at c h n u m b er o n t h e C o n M e d 
p a g e i n e C R F.  
 
6. 5. 2.  
M e di c ati o n s t o b e U s e d wit h C a uti o n wit h X e vi n a p a nt or M at c h e d 
Pl a c e b o   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
6. 5. 3.  
Pr o hi bit e d C o n c o mit a nt M e di c ati o n s   
6. 5. 3. 1.  
Pr o hi bit e d M e di c ati o n s wit h X e vi n a p a nt or M at c h e d Pl a c e b o   
Li v e -att e n u at e d v a c ci n ati o n s d uri n g tr e at m e nt wit h x e vi n a p a nt/ m at c h e d pl a c e b o a n d u p t o 9 0 
d a y s aft er t h e e n d of tr e at m e nt ar e pr o hi bit e d.  
Ot h er pr e p ar ati o n s a n d 
m e di c ati o n s s u c h a s t h o s e li st e d b el o w ar e stri ctl y pr o hi bit e d i n 
c o m bi n ati o n wit h x e vi n a p a nt or m at c h e d pl a c e b o.  
 
6. 5. 3. 1. 1.  
F o o d a n d H er b al Pr e p ar ati o n s   
Gr a p efr uit j ui c e a n d gr a p efr uit -c o nt ai ni n g pr o d u ct s ( P -g p i n hi bit or s) 
m a y l e a d t o i n cr e a s e d 
x e vi n a p a nt e x p o s ur e.  
St J o h n’ s W ort ( = H y p eri c u m p erf or at u m , mill e p ert ui s) a nd St J o h n’ s W ort -c o nt ai ni n g pr o d u ct s ( P -
g p i n d u c er s) m a y l e a d t o d e cr e a s e d x e vi n a p a nt e x p o s ur e.  
 
  
 
 
 
 
 
  
  
 
  
 
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
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6. 5. 3. 2.  
R e c o m bi n a nt H u m a n Er yt hr o p oi eti n a n d D eri v at e s   
R e c o m bi n a nt h u m a n er yt hr o p oi eti n ( E P O) i s n ot all o w e d t hr o u g h o ut t h e e ntir e d ur ati o n of t h e 
st u d y.  
Pr e cli ni c al a n d cli ni c al st u di e s s h o w e d t h at a ut o c ri n e or p ar a cri n e er yt hr o p oi eti n si g n ali n g c a n 
e n h a n c e c a n c er i n v a si o n i n S C C H N a n d n e g ati v el y aff e ct s p ati e nt o ut c o m e i n t er m s of O S a n d 
l o c al-r e gi o n al P F S (H e n k e  et al. 2 0 0 3 ; L a m bi n  et al. 2 0 0 9 ). 
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To investigate whether EPO signaling might play a direct role in SCCHN progression, 
Mohyeldin A. et al examined the immunohistochemical expression of EPO and EpoR proteins in 
biopsy samples obtained from oral cavity, oropharyngeal, hypopharyngeal, and laryngeal lesions 
of patients not previously treated with recombinant human EPO (Mohyeldin et al. 2005). The 
analysis revealed high levels of both EPO and EpoR expression in the carcinomas examined. In 
normal tissues, EpoR staining was low and limited to the basal epithelial layer. Strong EpoR 
staining was seen throughout the dysplastic epithelium, in invasive carcinoma cells, and in lymph 
node metastases. 
6.5.3.3. 
Prohibited or Concomitant Use of Traditional Chinese Medicines  
Any traditional Chinese medication with approval for use as anticancer treatment (regardless of 
the type of cancer) will not be permitted during study treatment. Traditional Chinese medicines for 
indications other than anticancer treatment, such as supportive care, may be administered at the 
discretion of the Investigator. Any traditional Chinese medicines or herbal supplement, if known to 
be strong inhibitors/inducers of CYP3A4 or inhibitors of P-gp, will not be permitted. Use of 
traditional Chinese medicines as part of next line of anticancer treatment should be documented 
as such. 
6.5.3.4. 
Prohibited Medications and Medications to be Used with Caution 
with Cisplatin or Carboplatin  
Prohibited medications 
Platinum-based cytotoxic agents may reduce the digestive absorption of phenytoin and 
fosphenytoin, resulting in reduced epilepsy control and risk of exacerbation of convulsions. 
Therefore, both phenytoin and fosphenytoin are prohibited during the combination therapy period. 
Granulocyte-Colony Stimulating Factors (G-CSF) are not allowed throughout the screening period 
and for prophylaxis. Nevertheless, for participants presenting with febrile neutropenia who have 
risk factors for infection-related complications or poor clinical outcome, therapeutic G-CSF 
including secondary prophylaxis should be considered (Becker et al. 2020). Features associated 
with poor outcome include age >65 years, sepsis syndrome, ANC <100 neutrophils/m3, anticipated 
prolonged (>10 days) neutropenia, pneumonia or other clinically documented infection, invasive 
fungal infections, and hospitalization at the time of fever. 
 
Medications to be used with caution 
Please consult and follow the instructions provided in your local label. 
6.5.3.5. 
Use of Other Investigational Agents and Devices  
Treatment with an investigational agent other than xevinapant/placebo, treatment or use of an 
investigational device within 4 weeks of the first dose of study treatment or during study treatment 
are prohibited.  
6.5.3.6. 
Use of Anticancer Treatments  
Treatment with other anticancer treatments within 4 weeks of the first dose of study treatment or 
during study treatment is prohibited.  
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6.5.4. 
Rescue Therapy and Supportive Care  
6.5.4.1. 
Rescue Therapy  
Not applicable 
6.5.4.2. 
Supportive Care  
6.5.4.2.1. 
Nutritional Support  
All participants should be screened for nutritional risk and early enteral nutrition. Nutrition status 
should be evaluated Q3W during the treatment period. 
A percutaneous endoscopic gastrostomy or nasogastric tube can be placed prophylactically 
necessary depending on the participant’s nutritional status and/or swallowing capabilities 
according to the Investigator’s judgment. 
 
6.5.4.2.2. 
Dental Care  
Patients with head and neck cancers are at risk of oral and dental complications after RT because 
of treatment-induced xerostomia and salivary gland dysfunction, which are associated with 
increased dental caries. 
In addition, RT to the dental hard tissues is associated with bone demineralization and trismus of 
the masticatory muscles. Using IMRT and limiting the RT dose to the teeth have been shown to 
decrease both xerostomia and damage to the teeth (Adam S. Garden 2017; NCCN 2019). 
Dental/oral evaluation and management can help decrease dental caries and associated 
problems such as dentoalveolar infection and osteoradionecrosis. 
The recommended dental/oral evaluations before, during, and after RT are summarized below. 
A dental/oral treatment plan should be implemented before RT and should include the following: 
• 
Eliminating potential sources of infection. 
• 
Performing any dental extractions preferably at least 2 weeks before RT. 
• 
Treating active dental caries and periodontal disease. 
• 
Treating oral candidiasis. 
• 
Educating participants about preventive strategies. 
Some of the strategies to decrease oral and dental complications include: 
• 
Decrease dry mouth (e.g., by using salivary substitutes and stimulation). 
• 
Decrease dental caries (e.g., by using topical fluoride). 
• 
Decrease dentoalveolar infection (e.g., with frequent evaluations to detect and treat 
disease promptly). 
• 
Decrease osteoradionecrosis (e.g., by extracting teeth before RT). 
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• 
Decrease trismus of the masticatory muscles (e.g., by using custom mouth-opening 
devices to maintain range of motion). 
• 
Have participants undergo evaluations during and after treatment to help minimize 
complications. 
During and after treatment, the goals of dental/oral management include: 
• 
Managing xerostomia. 
• 
Preventing trismus. 
• 
Detecting and treating oral candidiasis. 
Additional goals after treatment include: 
• 
Preventing and treating dental caries. 
• 
Preventing post-radiation osteonecrosis. 
• 
Preventing oral candidiasis. 
Dental/oral evaluation can be performed by the dental clinic team of the site or by an external 
dentist. 
 
6.5.4.2.3. 
Pain  
The management of pain should be done according to severity and recommended drugs as per 
institutional guidelines. Please, review Table 6-5 before using concomitant medications. 
 
7. STUDY INTERVENTION DISCONTINUATION, END OF STUDY AND 
EARLY STUDY TERMINATION  
7.1. 
Study Intervention Discontinuation  
Study treatments (i.e., xevinapant/matched placebo, cisplatin/carboplatin and IMRT) must be 
discontinued under the following circumstances: 
• 
Disease progression, including clinical progression as judged by the Investigator, 
treatment failure, local or distant relapse, second cancers, or start of any new anticancer 
treatment including salvage surgery (see EFS definition in Table 3-1 for further details). 
• 
Participant withdrawal of consent for treatment. 
Participants may voluntarily withdraw consent at any time. If such withdrawal occurs, every 
effort should be made by the Investigator to determine the primary/underlying reason for 
this decision, which should be recorded in the EOT eCRF. The participant should be 
encouraged to remain on study to be followed for survival and/or efficacy assessments. 
• 
Unacceptable toxicity/AEs, that result in a significant risk to the participant’s safety. 
Participants who are removed from study treatment due to AEs are to be treated and 
followed up for these AEs according to standard medical practices. 
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• 
Any protocol deviation that results in a significant risk to the participant’s safety. 
• 
Pregnancy. 
• 
Investigator decision in the participant’s best interest. 
The primary reason for this decision (e.g., lack of efficacy, AE) must be recorded in the 
eCRF. 
• 
Early study termination by the Sponsor, Steering Committee, the Investigator, the IEC/IRB 
or the Regulatory Agencies (Section 7.4). 
 
7.2. 
End of Study  
The EOS will be triggered once 386 OS events are observed or the last on-study participant has 
reached his/her 60-months post-randomization visit. At this timepoint (± 2 months), all participants 
who have not previously discontinued from the study prematurely will undergo the EOS 
assessments and will be considered as having completed the study. 
 
7.3. 
Premature Study Withdrawal (Participant Level)  
Premature withdrawal from the study can be triggered by: 
• 
Participant withdrawal of consent for study participation. 
Participants may voluntarily withdraw consent at any time. If such withdrawal occurs, every 
effort should be made by the Investigator to determine the primary/underlying reason for 
this decision and that should be recorded as reason in the End of Study eCRF i.e., if the 
underlying reason for the decision is toxicity (e.g., AE) this should be recorded as such 
and the Investigator has to follow up the participant until the AE or SAE is resolved. 
• 
At the discretion of the Investigator for safety, behavioral, compliance, or administrative 
reasons (e.g., disruption of operations due to natural disasters, interruption of laboratory 
or facility accreditation, participant moving to another country, resignation of key staff). 
The primary reason for this decision must be recorded in the CRF. 
• 
Participant lost to follow-up (Section 7.5). 
• 
Death. 
• 
Early study termination by the Sponsor, Steering Committee, the Investigator, the IEC/IRB 
or the Regulatory Agencies (Section 7.4). 
Should a participant be withdrawn from the study, EOS assessments should be performed prior 
to any further therapeutic intervention whenever possible. Results of these assessments are to be 
recorded in the eCRF, together with a description of the reasons for study discontinuation. 
 
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7.4. 
Early Study Termination by the Sponsor, Steering Committee, the 
Investigator, the IEC/IRB or the Regulatory Agencies  
The study may be prematurely terminated by the Sponsor, Steering Committee, the Investigator, 
the IEC/IRB or the Regulatory Agencies at any time, for the following reasons: 
• 
Medical or ethical reasons impacting the continuation of the study. 
• 
Difficulties in recruiting participants. 
• 
Ineffectiveness of the study medication. 
• 
Onset of adverse reactions of investigational drug that are unacceptable and unknown to 
date with regards to their nature, severity and duration; or an unexpected incidence of any 
unacceptable adverse reaction. 
• 
Business reasons. 
If the study is prematurely terminated, the Investigator must promptly inform the study participants 
and ensure that they receive appropriate therapy and follow-up. All assessments described in 
Section 7.1 for premature withdrawal of the participant should be followed. The Investigator may 
be informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the participant’s interests. 
The Investigator will be responsible for informing the IRB and/or IEC of the early termination of 
the study. If the IEC/IRB terminates the study or suspends its approval, the Investigator should 
promptly inform the Sponsor and provide a detailed written explanation of the termination. 
Please refer to Section 7.3 for study discontinuation at the participant level. 
 
7.5. 
Lost to Follow-Up  
A participant will be considered lost to follow-up if he or she fails to return for the EOS assessments 
within the permitted EOS visit window and is unable to be contacted by the study site staff. 
The site should make every effort to regain contact with the participant and reschedule the missed 
visit as quickly as possible. These contact attempts should be documented in the participant’s 
medical record or study file. Participants lost to follow-up will not be replaced. 
 
7.6. 
Participant Replacement  
Participants will not be replaced. 
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8. STUDY ASSESSMENTS AND PROCEDURES  
Please refer to Section 1.3, Table 1-1 and Table 1-2 for the schedule of assessments. It may be 
necessary to perform these assessments at unscheduled timepoints if deemed clinically 
necessary by the Investigator. 
8.1. 
Screening Procedure  
Once a participant has signed the ICF (see Section 11.1.1), an identification number will be 
assigned to him/her and the study related screening procedures will start. The screening period 
will last up to 28 days before the start of the treatment (C1D1). 
Protocol waivers or exemptions are not allowed. 
A participant will be randomized into the study after he/she has signed the ICF, all eligibility criteria 
have been met and the IMRT plan has been sent to the RT-QA Review Center (see Section 
11.2.2). The IMRT plan must be approved by the RT-QA Review Center prior to the start of the 
IMRT. 
The central laboratory assessments needed for participant eligibility are specified in Table 8-2. 
Local laboratory results only for HBV/HCV/HIV tests (obtained within 2 weeks before ICF 
signature) and HPV status (also see Section 8.1.2) may be accepted if report is available. If the 
previous central laboratory results are older than 7 days, the hematologic, renal and hepatic 
laboratory assessments should be rechecked by a local laboratory before the first dose 
administration. 
No participant replacement will be allowed. All randomized participants will be included in the 
Intent-to-treat (ITT) population. 
8.1.1. 
Baseline Disease Characteristics and Assessments  
Baseline participant and disease characteristics will be assessed during the 28-day screening 
period. 
The following should be performed prior to randomization to confirm eligibility and disease staging: 
demographics, vital signs, physical examination, weight, height, ECOG performance status 
(ECOG PS), ECG, nutritional status, dental examination, audiometry, coagulogram, laboratory 
tests (see Section 8.3.7 for further details), 18F-FDG-PET, i.v. contrast-enhanced CT-scan or MRI 
of head and neck, CT-scan of chest, and fiberoptic endoscopy. 
Medical history includes tobacco and alcohol consumption history and habits. 
Tumor staging should be established using the AJCC/TNM Staging System, 8th Ed., based on 
radiological imaging. Please refer to Section 8.2.1 for further details on radiological imaging. 
If several ECGs (scheduled and unscheduled) are performed during the screening, the most 
recent results should be recorded in the eCRF. 
18F-FDG-PET, i.v. contrast-enhanced CT-scan or MRI of head and neck, and CT-scan of chest 
are only accepted if they are performed within 4 weeks before randomization. Dental examination, 
audiometry, HBV/HCV/HIV tests, and fiberoptic endoscopy performed within 2 weeks before ICF 
signature do not have to be repeated during screening. 
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Results from the central laboratory should be used for defining participant eligibility during 
screening, except for: 
• 
HBV/HCV/HIV tests that may be performed by a local laboratory within 2 weeks before ICF 
signature (see Section 8.3.7). 
• 
HPV status by p16 IHC that may be obtained locally (see Section 8.1.2). 
 
8.1.2. 
HPV Status in Participants with OPC  
In participants with OPC, primary tumors must be HPV-negative, determined by p16 IHC.  
p16 cutoff for determination of HPV status is defined as following: For HPV status of OPC 
participants, p16 expression by IHC is scored as positive if a total H-Score ≥ 210 or ≥ 70% of the 
tumor cells with 3+ staining intensity in nucleus and cytoplasm. H-Score should be calculated by 
the formula: H = [% weak (1+)x1] + [% moderate (2+)x2] + [% strong (3+)x3].  
Results obtained prior to the participant’s consent to participation in the study are acceptable, 
provided a report is available. If no report is available for HPV status by p16 IHC, the assessment 
can be done locally on an archived tumor sample. 
If the site is not able to perform HPV testing by p16 IHC, it will be evaluated by a central pathology 
laboratory designated by the Sponsor. In this case, randomization into the study can only occur 
after confirmation of HPV-negative status has been communicated to the site. 
The results of existing local data must be captured on the appropriate eCRF upon enrolment into 
the study after the participant has signed the ICF. 
 
8.1.3. 
Highly Effective Contraceptive Measures and Pregnancy Test  
To be enrolled in the study women of childbearing potential and men with female partners of 
childbearing potential must agree to use highly effective contraceptive measure(s) from ICF 
signature to 6 months after completing chemotherapy treatment or 3 months after last dose of 
xevinapant/matched placebo, whichever is the latest (see inclusion criteria 11 in Section 5). 
Non-sterilized males who are sexually active with a female partner of childbearing potential must 
agree to use condom and spermicide from ICF signature to 6 months after last administration of 
chemotherapy or 3 months after last dose of xevinapant/matched placebo, whichever is the latest 
(see inclusion criteria 11 in Section 5). Because male condom and spermicide is not a highly 
effective contraception method it is strongly recommended that female partners of male study 
participants use highly effective contraceptive method(s) throughout this period. 
Contraceptive measures which are considered highly effective comprise combined (estrogen 
and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing 
system, bilateral tubal occlusion, vasectomized partner and sexual abstinence. 
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If a hormonal contraception is chosen, the use of a barrier method (preferably male condom) is 
mandatory due to potential risk of CYP3A4/5 induction by xevinapant that may reduce hormonal 
contraception efficacy. 
Abstinence is acceptable only if it is consistent with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of birth control. 
Females without childbearing potential, defined as those who are surgically sterile (i.e., bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or those who are 
post-menopausal (defined as 12 months with no menses without an alternative medical cause) 
and have a follicle-stimulating hormone level in the laboratory normal range for post-menopausal 
phase at screening, do not need a pregnancy test. 
Serum pregnancy test (β-HCG) will be conducted during screening by a central laboratory in 
women of childbearing potential (see Table 8-2). On C1D1, negative serum pregnancy status 
should be rechecked locally by serum or urine test only if the previous central laboratory result is 
older than 7 days. After C1D1, serum or urine tests should be performed locally according to 
schedule presented in Table 1-1 and Table 1-2 
Should a pregnancy still occur, all study treatments should be discontinued immediately. 
The Sponsor should be notified of any pregnancy that occurs in female participants or partners of 
male participants during participation in studies with xevinapant by submitting a specific pregnancy 
form. Any reports of pregnancy in participants or partners of participants will be followed up as 
described in Section 9.4.2. 
8.2. 
Efficacy Assessments  
Assessment of tumor response to treatment will be assessed locally and centrally according to 
the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) but will also take into 
consideration clinical, anatomopathological, and functional assessments of the tumor, as 
described in Appendix 13.5. 
Tumor assessment and HRQL questionnaires or assessments should be continued until disease 
progression (as per RECIST v1.1) occurs or Month 60 post-randomization, whichever occurs first. 
Participants who progress (as per RECIST v1.1) will enter the OS follow-up period at the time of 
the event and will be followed up for survival status at least every 3 months, until the EOS (see 
Section 7.2). 
In case of premature discontinuation of treatment in participants without disease progression 
according to RECIST v1.1 (e.g., unacceptable toxicity), efficacy assessments will continue to be 
performed until an EFS event has been determined or Month 60 post-randomization, whichever 
occurs first. 
8.2.1. 
Radiological Assessment  
For each participant, the same radiological method for head and neck and for chest must be used 
throughout the study. The schedule of collection of i.v. contrast-enhanced CT-scan or MRI of head 
and neck (which cover the orbits), CT-scan of the chest and 18F-FDG-PET scan (from the skull 
base to the proximal upper legs) is provided in Table 1-1 and Table 1-2. 
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18F-FDG-PET/CT-scan is preferred to facilitate pre-and post-treatment evaluation of metabolic 
response and the need for post-treatment neck dissection. If physical examination and imaging 
suggest residual disease at the primary site, a biopsy will be performed to confirm residual 
disease; otherwise, participants will undergo serial follow-up. 
Additional imaging assessments may be performed at any time during the study at the 
Investigator’s discretion to support the efficacy evaluations for a participant. Clinical progressive 
disease (PD) is recommended to be confirmed by imaging and/or endoscopy (i.e., biopsy). 
If an off-schedule imaging assessment is performed because progression is suspected, 
subsequent assessments should be performed in accordance with the original imaging schedule. 
Measurability of the tumor at baseline 
At baseline, participants may be included with measurable disease or with only evaluable, non-
measurable disease according to RECIST v1.1 and as assessed by the Investigator. Measurable 
disease is defined as the presence of at least one measurable nodal or non-nodal lesion. The 
assessment of participants at baseline according to RECIST v1.1 is covered in Appendix 13.5.  
Non-measurable disease means that only non-measurable lesions exist at baseline. Guidance on 
how participants with only non-measurable disease at baseline will be evaluated for response and 
progression based on RECIST v1.1 is also defined in Appendix 13.5.  
In this study, radiological response confirmation is not required either for partial or complete 
response. 
For the purposes of the primary endpoint and to minimize bias, a BIRC will perform an independent 
assessment based on all efficacy imaging reading, review of selected clinical data and 
anatomopathological results. 
Hence, all study imaging performed, including any off-schedule imaging performed, and 
anatomopathological assessments should be submitted to the designated imaging vendor for 
quality control and review by the BIRC, promptly after acquisition. 
8.2.2. 
Clinical Assessment  
All participants will be assessed at the EOT visit (20 [±1] weeks) with clinical/radiological exams 
on: 
• 
18F-FDG-PET/CT scans for determining the overall clinical outcomes and the need for 
nodal dissection (18F-FDG-PET/CT should be ordered before examination under 
anesthesia with endoscopy, biopsies, and tonsillectomy, to help identify potential primary 
sites before any intervention occurs). 
• 
Ear, nose and throat, and fiberoptic endoscopy. 
These clinical assessments are to be performed according to the schedule presented in Table 1-1 
and Table 1-2 
If the EOT scan was positive AND the participant underwent salvage surgery and END, no further 
18F-FDG-PET scans should be performed. If EOT results were inconclusive AND the participant 
did not undergo salvage surgery and END, the 18F-FDG-PET scan should be repeated 12 weeks 
after EOT (Week 31±2weeks). 
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Clinical PD must be verified by imaging and/or biopsy, wherever possible. The presence or 
absence of residual viable tumor cells will be determined via a histopathological examination. 
Negative 18F-FDG-PET at baseline, with a positive 18F-FDG-PET at EOT is a sign of PD based on 
a new lesion if considered related to the disease under study (a confirmatory biopsy should be 
performed whenever possible). Further details of the interpretation of 18F-FDG-PET in this study 
are supplied in Appendix 13.5. 
In case of doubt of a clinical local-regional recurrence or distant metastasis before the EOT, 
imaging by CT/MRI scan should be performed to verify disease progression. 
During the follow-up period the participants will undergo ear, nose and throat examination, 
fiberoptic endoscopy and MRI and/or chemotherapy as per the schedule presented in Table 1-2. 
Clinical assessment process: 
If the primary site is cleared of residual disease but residual disease at the cervical nodal basin is 
suggested by imaging/clinical evaluation, then END will be performed unless a cytologic sampling 
of the node is negative. Post-treatment “planned” neck dissection will be defined as being 
performed for residual disease and before 22 weeks after randomization. 
Positive neck specimens removed before 22 weeks after randomization will be considered part of 
the initial treatment plan and not considered as failures of initial management; positive specimens 
upon neck dissection at 22 weeks and beyond will be considered regional failures. 
Such post-treatment consolidation neck dissections will encompass only the areas initially 
involved in the side of the neck in question (typically the involved area(s) and the adjacent 
immediate level). The extent of neck dissections performed for nodal recurrence, nodal 
progression, or salvage of disease at the primary will be determined by the treating surgeon. 
Any treatment intervention in relation to the disease under study, including biopsies, END or 
surgery on the primary tumor as well as the anatomical site(s) and histopathology results must be 
reported in the eCRF. 
If histopathology results or other clinical data are not consistent with the radiology report, then this 
information will be taken into account for the determination of tumor status according to the 
decision tree below (Figure 8-1).  
 
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8.3. 
Safety Assessments  
Safety assessments will be performed according to the schedule in Table 1-1 and Table 1-3 and 
are further described below. 
 
8.3.1. 
Physical Examination  
The examination will include general appearance, sclera, cardiovascular system, pulmonary 
system, neurologic system, skin and gastrointestinal system. Abnormalities are to be recorded as 
medical history if started prior to the ICF signature or as an AE if started on or after ICF signature. 
 
8.3.2. 
Vital Signs and ECOG Performance Status  
Weight (to the nearest 0.1 kilogram or pound), height, ECOG performance score (see Appendix 
13.1) and vital signs will be collected. Height will be measured at screening only. 
Vital signs will include systolic/diastolic blood pressure (in sitting position after 10 minutes of 
supine rest), heart rate (after 10 minutes of supine rest), respiratory rate, and temperature. 
 
8.3.3. 
Nutritional Status  
Swallowing/nutritional status is to be done to determine if nasogastric tube, percutaneous 
endoscopic gastrostomy, or percutaneous endoscopic jejunostomy tube placement is needed. 
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An examination under anesthesia is recommended, including a direct laryngoscopy, 
bronchoscopy, esophagoscopy, and nasopharyngoscopy. At this point a biopsy can be taken if 
not yet readily available and if necessary. 
A feeding tube is strongly recommended if the participant has swallowing disorders and / or weight 
loss. A feeding tube is mandatory if the participant has grade 3 dysphagia. 
 
8.3.4. 
Dental Examination  
A dental examination is to be performed by the site's dental clinic team according to institutional 
guidelines or by an external dentist (see Section 6.5.4.2.2). 
 
8.3.5. 
Audiometry  
An audiometry must be performed at screening. In addition, hearing clinical evaluation and 
audiometry should be performed at C2D1 and C3D1 if clinically indicated (except for France, see 
Appendix 13.6) and at any time if clinically indicated as per institutional or national guidelines. 
During the follow-up period, an audiometry is to be performed only if clinically indicated, as per 
institutional or national guidelines. 
 
8.3.6. 
Electrocardiograms  
A standard single 12-lead ECG will be recorded after 10 minutes of supine rest according to the 
schedule shown in Table 8-1. 
 
Table 8-1 ECG collection plan  
Study visit or cycle 
Day 
Time relevant to dosing 
Screening 
-28 to -1 
n.a. 
Cycle 1 
 
1 
Predosea 
0.5-2 hours postdose  
4-6 hours postdose 
8 
Predosea 
0.5-2 hours postdose  
n.a.: not applicable.  
a 
To be performed prior to blood sampling. 
  
 
  
 
If several ECGs (scheduled and unscheduled) are performed during the screening, the latest 
results should be recorded and used. 
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If ECGs are performed at the same time point as blood sampling (
 safety laboratory tests), 
ECG readings should be taken prior to 
 sampling. 
All ECG readings will be performed locally by the Investigator, or a cardiologist will be consulted 
if clinically indicated. 
Additional ECGs can be performed if clinically indicated. 
Abnormal ECG findings 
In case of abnormal ECG findings (e.g., QTcF prolongation >30 ms compared to baseline, or 
QTcF interval >500 milliseconds, Torsade de pointes, ventricular tachycardia, ventricular 
fibrillation, flutter or any other new cardiac abnormality), triplicate ECG readings will be performed. 
If the abnormal ECG finding is confirmed after triplicate ECG readings, the participant should be 
referred to a local cardiologist. 
Significant QTcF prolongation is defined as an interval >500 milliseconds (ms) or an interval which 
increases by 60 ms over baseline. 
Management of participants with significant QTcF prolongation 
If the QTcF prolongation is confirmed by either criterion (i.e., QTcF interval >500 ms or >60 ms 
increase from baseline) the following actions will be taken (see also Table 6-1): 
• 
The treatment with xevinapant/matched placebo must be interrupted. 
• 
The participant will be monitored including assessment of electrolytes in plasma 
(potassium calcium and magnesium), treated appropriately and closely followed (ECGs at 
least 3 times per week) until resolution to within 30 ms from baseline or QTcF <480ms. 
• 
Stop any concomitant medication known to cause QTc prolongation. 
• 
The participant will be referred to a cardiologist. 
• 
The medical monitor will be consulted prior to administering further xevinapant/matched 
placebo doses. 
• 
If the QTcF interval does not return to within 30 ms of baseline or <480 ms within 14 days, 
xevinapant/matched placebo must be permanently discontinued. 
• 
For cisplatin/carboplatin, at the first occurrence, action taken for these agents is based on 
the Investigator’s judgment. At the second occurrence, consider permanent 
discontinuation. 
If the prolongation is confirmed by both criteria (i.e., QTcF interval > 500 ms and > 60 ms increase 
from baseline) the following actions will be taken: 
• 
The treatment with xevinapant/matched placebo and cisplatin/carboplatin must be 
permanently discontinued. 
• 
The participant will be monitored including assessment of electrolytes in plasma 
(potassium calcium and magnesium), treated appropriately and closely followed (ECGs at 
least 3 times per week) until resolution to within 30 ms to baseline. 
• 
Stop any concomitant medication known to cause QTc prolongation. 
• 
The participant will be referred to a local cardiologist. 
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8.3.7. 
Laboratory Tests: Hematology, Biochemistry, Urinalysis, Pregnancy 
Tests  
Laboratory assessments and pregnancy test should be performed by a central laboratory 
designated by the Sponsor and/or by a local laboratory, according to instructions in Table 8-2 
below. 
These laboratory assessments are to be performed according to the schedule presented in 
Table 1-1 and Table 1-2 
On C1D1, hematologic, renal and hepatic laboratory assessments required for inclusion (see 
criteria 9 -Section 5), and for defining suitability for cisplatin administration (see Table 8-2 and 
Section 6.1.2.2) should be assessed by a central laboratory. If the previous central laboratory 
results are older than 7 days, the hematologic, renal and hepatic laboratory assessments should 
be rechecked by a local laboratory before the first dose administration. 
On C1D1, negative serum pregnancy status should also be rechecked locally by serum or urine 
test only if the previous central laboratory result is older than 7 days. 
On C2D1 and C3D1, suitability for chemotherapy administration (see Table 8-2 and 
Section 6.1.2.2) should be evaluated based on local laboratory values irrespectively of the 
samples sent to the central laboratory. 
Renal function must be monitored 48 hours (±12 hours) after cisplatin infusion (i.e C1D4, C2D4, 
C3D4) based on local laboratory values of creatinine, eGFR, sodium, potassium, calcium, and 
magnesium. 
The initial pregnancy test should be performed on serum during screening period by a central 
laboratory (Table 8-2 and Section 8.1.3). Subsequent pregnancy tests will be performed locally 
using urine or serum according to the schedule in Table 1-1 andTable 1-2, or if clinically indicated. 
 
Table 8-2 Assessments to be performed by a central laboratory or by a local laboratory according 
to study visit  
Visit 
Central laboratory designated by the 
Sponsor 
Local laboratory 
During screening 
o 
HBV/HCV/HIV tests if no local results 
obtained within 2 weeks before ICF 
signature 
o 
HPV status by p16 IHC if no available 
report and test not available locally 
o 
Blood hematology (Table 8-3) 
o 
Blood biochemistry (Table 8-3) 
o 
Serum pregnancy test 
o 
Urinalysis (Table 8-3) 
o 
Local results within 2 weeks before ICF 
signature accepted for HBV/HCV/HIV 
tests 
o 
HPV status by p16 IHC if no available 
report 
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Visit 
Central laboratory designated by the 
Sponsor 
Local laboratory 
C1D1 
All hematology and biochemistry assessments 
(full panel) mentioned in Table 8-3. 
 
The following assessments should be 
performed locally if the previous central 
laboratory results are older than 7 days: 
o 
Laboratory assessments specified in 
inclusion criteria 9 and assessments 
required to evaluate suitability for cisplatin: 
eGFR, ANC, platelet counts, hemoglobin, 
AST, ALT, total bilirubin 
o 
Serum or urine pregnancy test 
 
If central laboratory assessments for eGFR, 
ANC, platelet counts, hemoglobin, AST, ALT 
and total bilirubin were performed within 7 days 
before C1D1, they should not be repeated 
locally on C1D1. 
 
C2D1 and C3D1 
o 
All hematology and biochemistry 
assessments (full panel) mentioned in 
Table 8-3. 
o 
Coagulogram (Table 8-3) 
o 
Urinalysis (Table 8-3) 
o 
Laboratory assessments required to 
evaluate suitability for chemotherapy 
administration: eGFR, platelet counts, 
ANC, hemoglobin rate 
o 
Serum or urine pregnancy test 
All visits after 
randomization, except 
C1D1; C2D1 and C3D1 
Hematology, coagulogram, blood chemistry and 
urinalysis assessments (Table 8-3), to be 
performed according to schedule presented in 
Table 1-1 and Table 1-2 
Serum or urine pregnancy test 
Renal function 
monitoring 48 hours 
(±12 hours) after 
cisplatin infusion 
(C1D4, C2D4, C3D4) 
n.a. 
Creatinine, eGFR 
Sodium, potassium, calcium 
magnesium 
Abbreviations: ALT: alanine aminotransferase; ANC: absolute neutrophil count; AST: aspartate aminotransferase; 
CxDx: cycle x Day x; eGFR: estimated glomerular filtration rate; HBV: Hepatitis B virus; HCV: Hepatitis C virus; 
HIV: Human 
immunodeficiency 
virus; 
HPV: human papillomavirus; 
ICF: 
informed 
consent 
form; 
IHC: 
immunohistochemistry; n.a.: not applicable. 
 
Blood samples for hematology, biochemistry and coagulogram assessments should be taken 
before treatment administration., Blood sample for coagulogram should be collected 
 
 (see schedule of relevant visits in Table 1-1). 
Details on all laboratory procedures, collections, shipment of samples and reporting of results, 
alerting of extreme values and notable values by the central laboratory are provided to 
Investigators in the laboratory manual of extreme values. 
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The Investigator is responsible for reviewing all laboratory reports for participants during the study 
and evaluating any abnormalities for clinical significance. 
If a local laboratory is used, the local laboratory values will have to be recorded on the Local 
Laboratory Results eCRF if clinically significant. 
Furthermore, local laboratory assessments may also be performed according to medical needs 
(e.g., during medical emergencies, or for treatment-related decisions, etc.) when the Investigator 
needs quick results to make treatment decisions. 
Clinically significant laboratory abnormalities occurring since the ICF signature are to be recorded 
in the eCRF as AEs. 
Further details on sample collection, handling and shipment will be provided in the laboratory 
manual. 
 
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Table 8-3 Assessments to be performed by a central laboratory designated by the Sponsor  
Virology 
HBV: HBV sAg and Anti-HepB core IgG 
HCV: HCV-antibody and HCV-RNA by PCR 
HIV1/2 
Hematology 
White blood cell count (total and differential) 
Red Blood cell count, Hemoglobin 
Platelet count 
ANC 
Coagulogram 
Prothrombin Time or INR, if applicable (e.g., under oral anticoagulation medication) 
Activated partial thromboplastin time 
Fibrinogen 
Blood 
Biochemistry 
(full panel) 
Creatinine and 
eGFRa 
Total protein 
Albumin 
Total bilirubin 
(If >ULN: direct 
bilirubin should 
also be 
measured) 
ALP 
AST 
ALT 
C-reactive 
protein 
Amylase 
Lipase 
Sodium 
Potassium 
Calcium 
Magnesium 
Urea 
Uric acid 
Blood 
Biochemistry 
(minimum 
panel) 
Creatinine 
Total bilirubin 
(If >ULN: direct 
bilirubin should 
also be 
measured) 
ALT 
AST 
ALP 
Sodium 
Potassium 
Amylase 
Lipase 
Urea 
Urinalysis 
Dipstick test for: 
Red blood cells 
Protein 
Glucose 
Leucocytes 
Ketones 
 
Pregnancy 
test  
Serum pregnancy test (β-HCG) during screening in women of childbearing potential, local serum or urine 
tests thereafter. 
Abbreviations: ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANC: absolute neutrophil count; AST: 
aspartate aminotransferase; β-HCG: Human chorionic gonadotropin; eGFR: estimated glomerular filtration rate; HBV: 
hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; INR: International normalized ratio; sAg: 
surface antigen; ULN: upper limit of normal. 
a  
eGFR should be calculated using the using the Chronic Kidney Disease - Epidemiology Collaboration [CKD -EPI] 
creatinine formula. 
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8.3.8. 
Participant Diary  
Xevinapant/matched placebo will be dispensed by the medical staff or Pharmacist of the 
investigational sites. The participant will receive xevinapant or the matched placebo on an 
outpatient basis. 
On days 
 C1D2, C1D8, C2D2, C3D1, C3D2, participants should take their doses 
at the hospital, where the administration of xevinapant or the matched placebo will be supervised 
and recorded by the medical staff both in the eCRF and in the participant’s diary. In addition, the 
time of C1D7 dose taken at home needs to be recorded in both the eCRF and the participant’s 
diary. On days 
, at C3D8 and C4D1, xevinapant/placebo is taken, and the time of 
dosing (C3D8 and C4D1) must be recorded both in the eCRF and the participant’s diary. On 
C3D15, the last xevinapant/placebo dose timing (taken at home on C3D14) must be recorded 
both in the eCRF and the participant’s diary. 
The treatment schedule of xevinapant or the matched placebo is presented in Table 1-1 and 
Table 1-2. Participants will be instructed by the medical staff on how to self-administer xevinapant 
or the matched placebo at home. The participant should inform the medical staff of any missed or 
delayed doses. 
The paper diary will be dispensed to the participants according to the schedule presented in 
Table 1-1. They will be instructed on how to record xevinapant/matched placebo administration 
(i.e., date and time of the xevinapant intake should be recorded in the diary). 
Participants should record any skipped or miss-timed doses in their diary. 
Participants will be asked to bring the diary with them to their study visits. The diary will be 
collected and reviewed by site staff after the completion of each visit. 
8.3.9. 
Concomitant and Subsequent Neoplastic Medications  
Information about prior, concomitant, and subsequent therapies is provided in Section 6.5. 
8.3.10. 
Adverse Event Monitoring  
All AEs (including AESIs during the treatment period) will be collected from the time of ICF 
signature until the EOT visit. From the EOT visit until the EOS visit, only SAEs and late onset 
AESIs will be collected. 
Please refer to Section 9 for further details on AE collection. 
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8.5. 
Biological Specimen Collection  
8.5.1. 
Estimated Volume of Blood Samples  
For each participant enrolled, the estimated volumes of biological specimens collected during the 
study is listed in Table 8-4. 
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Table 8-4 Biological specimens collected during the study  
Sample type 
Type of assessment 
Volume/Size 
Blood/plasma 
Hematology, biochemistry, pharmacokinetics, 
pharmacogenetics 
180 mL 
 
 
8.6. 
Health-Related Quality of Life Assessments  
HRQL data will be collected to investigate the effects of xevinapant + CRT on participants’ reported 
well-being compared to placebo + CRT. 
The EORTC QLQ-C30 version 3.0, the EORTC QLQ-HN35 
 will be 
administered electronically: 
• 
The EORTC QLQ-C30 questionnaire captures QoL dimensions that are relevant for 
oncologic participants independently of the cancer type. 
• 
The EORTC QLQ-HN35 is a disease-specific supplementary module designed to capture 
dimensions that affect the QoL of head and neck cancer participants. 
 
 
 
Further details on the questionnaires are provided in Appendix 13.4. 
 
Administration of the HRQL questionnaires 
EORTC QLQ-HN35 and EORTC QLQ-C30 questionnaires will be administered 
according to the schedule shown in Table 1-1 and Table 1-2 The participant should also complete 
the EORTC 
 questionnaires at the time of progression. 
The baseline HRQL assessment should be performed prior to randomization. 
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Questionnaires should be completed by participants prior to any clinical tumor 
assessment and/or receiving results of any test, including disease status. Particular 
attention should be devoted to maximizing compliance. 
A nominated person in each center must be assigned to take responsibility for administration of 
HRQL forms. Participants should receive a short electronic training at screening, before 
completing the questionnaires. Participants should complete the questionnaires in a quiet, private 
area and any form of influence on their answers (e.g., conferring with friends, relatives, study 
personnel) should be avoided in order to ensure participant’s privacy and absence of bias. 
Completion of all 3 questionnaires is expected to take less than 25 minutes in total. 
 
 
9. ADVERSE EVENTS  
The Principal Investigator is responsible for ensuring that all staff involved in the study is familiar 
with the content of this section. 
Investigators will seek information on AEs at each safety evaluation. All AEs whether reported by 
the participant or noted by authorized study personnel, will be recorded in the participant’s medical 
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record and on the AE CRF. Their nature, severity, duration, and treatment, together with the 
Investigator's opinion as to their relationship to the drug, will be recorded. The Investigator will 
also indicate how the signs of the condition evolved. 
As needed, Sponsor may ask for copies of certain medical records (e.g. autopsy reports, 
supplemental lab reports, documents on medical history/concomitant medications, discharge 
letters), as supporting source documentation associated to AEs. All participant identifiers, except 
the participant number, will be redacted on these copies before submission to Sponsor. 
9.1. 
Definitions and Assessment Criteria  
9.1.1. 
Definition of Adverse Events  
The ICH Guidelines for GCP E6 (R1) defines an AE as: Any untoward medical occurrence in a 
participant or clinical investigation participant administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. 
Thus, any new sign, symptom or disease, or any clinically significant worsening of an existing sign, 
symptom or disease compared to the condition at the first visit should be considered as an AE, 
except if considered as associated with the underlying disease (for more details, see the 
paragraph below “Events that do not meet the definition of an AE”). 
Any abnormal laboratory test results or other safety assessments such as ECG findings, vital sign 
measurements), including those that worsen from baseline, and assessed to be clinically 
significant in the medical and scientific judgment of the Investigator, should be reported as an AE. 
Abnormal laboratory values that require an intervention such as a treatment or a change in the 
study treatment should also be reported as an AE. 
If clinical sequelae are associated with a laboratory abnormality, the diagnosis or medical condition 
should be reported (e.g., renal failure, hematuria) not the laboratory abnormality (e.g., elevated 
creatinine, urine red blood cell count increased). 
Events that do not meet the definition of an AE include: 
• 
Any clinically significant abnormal finding or other abnormal safety assessment that is 
associated with the underlying study disease, disease progression/recurrence unless 
judged by the Investigator to be more severe than expected for the participant’s condition. 
• 
Diagnostic testing and procedures: Testing and procedures should not be reported as AEs 
or SAEs, but rather the cause for the test or procedure should be reported. If a test or 
procedure is done to rule out a diagnosis, the sign or symptom leading to the 
test/procedure should be the event term, and the event term should only be updated to the 
diagnosis if/when the diagnosis is confirmed. Testing and procedures performed solely as 
screening measures should not be reported as AEs or SAEs. 
• 
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. 
• 
Lack of efficacy is not considered as an AE. 
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9.1.2. 
Definition of Serious Adverse Events  
An SAE is any AE that: 
• 
Results in death. 
• 
Is immediately life-threatening. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity. 
• 
Is a congenital anomaly/birth defect in offspring of the participant. 
• 
Is an important medical event that may jeopardize the participant or may require medical 
intervention to prevent one of the outcomes listed above. 
Medical or scientific judgment should be exercised in deciding whether or not expedited reporting 
is appropriate in this situation. Examples of medically important events are intensive treatment in 
an emergency department or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalizations; or development of drug dependency or drug abuse. 
An important medical event is an event that may not result in death, be life-threatening, or require 
hospitalization but may be considered an SAE when, based on appropriate medical judgment, it 
may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in the definitions for SAEs. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasia, or convulsions that do not result in hospitalization. 
Note: Inpatient hospitalization is considered to have occurred if the participant has had to stay 
overnight at the hospital. 
The criterion for prolongation of hospitalization is also defined as an extra night at the hospital 
than planned. Hospitalization may not constitute sufficient grounds to be considered as a SAE if 
it solely for the purpose of diagnostic tests (even if related to an AE). 
Pre-planned hospitalization: A hospitalization planned before signing the ICF is not considered an 
SAE, but rather a therapeutic intervention. However, if an event occurs during the pre-planned 
hospitalization that prolongs the hospitalization or meets any other SAE criteria, the event will be 
considered an SAE. Surgeries or interventions that were under consideration, but not performed 
before signing the ICF, will not be considered serious if they are performed after signing the ICF 
for a condition that has not changed from its baseline level. 
Social admissions: hospitalizations for social reasons, for example, solely for the administration of 
chemotherapy, or due to long travel distances are also not SAEs. 
9.1.3. 
Definition of Adverse Events of Special Interest  
An AESI is a noteworthy event of the particular study treatments (xevinapant/placebo, 
chemotherapy and IMRT) that can be appropriate to monitor closely. An AESI may be serious or 
non-serious and an AESI could include events that might be potential precursors or prodromal 
symptoms for more serious medical conditions in susceptible individuals. 
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The rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize 
and understand them in association with the study treatment administration (xevinapant/placebo, 
chemotherapy and IMRT). 
All AESIs during the treatment period should be recorded promptly in the eCRF. In addition, AESIs 
that are also SAEs should be reported to the Sponsor within 24 hours. 
 
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9.1.4. 
Definition of Adverse Event Reporting Period  
All AEs (including AESIs during treatment period) will be collected from the time of signature of 
ICF until the EOT visit. From the EOT visit until the EOS visit, only SAEs and late onset AESIs will 
be collected. 
 
9.1.5. 
Assessment of Relationship with Study Treatment(s)  
The Investigator or designee will determine the relationship between the AE and each study 
treatment according to the guidance below. 
 
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Table 9-1 Causal Attribution Guidance  
Is the AE/SAE suspected to be caused by the study treatments (xevinapant/placebo, chemotherapy, and IMRT) based 
on facts, evidence, science-based rationales, and clinical judgment? 
Reasonable 
causal 
relationship  
The temporal relationship of the AE/SAE to study treatment administration (xevinapant/placebo, 
chemotherapy and IMRT) makes a causal relationship possible, and other drugs, therapeutic interventions 
or underlying conditions do not provide sufficient explanation for the AE/SAE. 
No reasonable 
causal 
relationship 
The temporal relationship of the AE/SAE to study treatment administration (xevinapant/placebo, 
chemotherapy and IMRT) makes a causal relationship unlikely, or other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation for the AE/SAE.  
Abbreviations: AE: adverse event; IMRT: intensity-modulated radiotherapy; SAE: serious adverse event. 
The Investigator’s assessment of causality for individual AE reports is part of the study 
documentation process. 
Regardless of the “Yes” or “No” causality assessment for individual AE reports, Sponsor or 
designee will promptly evaluate all reported SAEs against cumulative product experience to 
identify and expeditiously communicate possible new safety findings to Investigators and 
applicable Regulatory Authorities. 
9.1.6. 
Assessment of Severity of Adverse Events  
AEs will be graded by the Investigator according to NCI-CTCAE, v5.0 criteria. The alternative 
definitions for grade 1, 2, 3, and 4 events mentioned in Table 9-2 should be used when the 
observed or reported AE is not in the NCI-CTCAE classification. 
 
Table 9-2 Adverse Event Grading (Severity) Scale  
Grade  Severity  
Alternative Description  
1  
Mild 
Awareness of sign or symptom, but easily tolerated; Transient or mild discomfort (<48 
hours); no interference with the participant’s daily activities; no medical 
intervention/therapy required.  
2  
Moderate 
Discomfort enough to cause mild to moderate interference with normal daily activities; No 
or minimal medical intervention/therapy required.  
3  
Severe 
Considerable interference with the participant’s daily activities; medical 
intervention/therapy required; hospitalization possible.  
4  
Very severe, life-
threatening or disabling 
Extreme limitation in activity; significant medical intervention/therapy required, 
hospitalization probable.  
5  
Death related to 
adverse event 
 
 
9.2. 
Procedures for Recording Adverse Events  
All AEs, whether expected or not, should be recorded immediately in the source document, and 
described on the AE form of the eCRF. 
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Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the CRF. Avoid colloquialisms and abbreviations. There is one eCRF for recording AEs or SAEs. 
Only one medical concept should be recorded in the event field on the Adverse Event CRF. 
 
9.2.1. 
Diagnosis Versus Signs and Symptoms  
If known, a diagnosis should be recorded on the eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). 
However, if a constellation of signs and/or symptoms cannot be medically characterized as a 
single diagnosis or syndrome at the time of reporting, each individual event should be recorded 
as an AE or SAE in the CRF. If it is an SAE, each individual event should be reported on a separate 
form. If a diagnosis is subsequently established, it should be reported as follow-up information. 
 
9.2.2. 
Adverse Events Occurring Secondary to Other Events  
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE in the CRF. 
However, medically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events in the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF. 
 
9.2.3. 
Persistent or Recurrent Adverse Events  
A persistent AE is one that extends continuously, without resolution between participant evaluation 
time points. Such events should only be recorded once in the eCRF unless their severity 
increases. If a persistent AE becomes more severe, it should be recorded again on the Adverse 
Event CRF. 
A recurrent AE is one that occurs and resolves between participant evaluation time points and 
subsequently recurs. All recurrent AEs should be recorded on the Adverse Event CRF. 
 
9.2.4. 
Abnormal Laboratory Values  
Only clinically significant laboratory abnormalities that require active management will be recorded 
as AEs or SAEs on the eCRF (e.g., abnormalities that require a treatment, study drug to be held 
or discontinued, more frequent follow-up assessments, further diagnostic investigation, etc.). If the 
clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., ALP and 
bilirubin 5 × the ULN associated with cholecystitis), only the diagnosis (e.g., cholecystitis) needs 
to be recorded on the Adverse Event CRF. 
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If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated serum potassium level should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit should not 
be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or etiology 
changes. 
 
9.2.5. 
Deaths  
All deaths occurring during the study will be reported on the death page of the eCRF. 
Deaths that are attributed by the Investigator as solely due to disease progression (death due to 
cancer under study) are not considered as SAEs. Conversely, medical events leading to death 
should be reported as SAEs if they cannot be determined to be exclusively due to the progression 
of the cancer under study or if they do not correspond to the expected pattern of progression of 
the disease under study. 
All other deaths are considered SAEs. They will be recorded on both the Death and SAE page of 
the eCRF: 
• 
The SAE verbatim term of the event or condition that caused or contributed to the fatal 
outcome should be recorded as a single medical concept. 
• 
If the cause of death is unknown and cannot be ascertained at the time of reporting, the 
verbatim term “Unexplained Death” should be recorded. 
• 
The Investigator must notify all other deaths within 24 hours of awareness (refer to Section 
9.3). 
 
9.3. 
Procedure for Reporting Serious Adverse Events to the Sponsor  
Notification of SAEs until the EOS visit will not depend on their relationship with study treatments: 
all SAEs and Serious Adverse Reactions (SARs) will be recorded until the EOS visit or until the 
study discontinuation/termination, whichever is the latest. 
The Investigator must notify the Sponsor of all SAEs within 24 hours of awareness by 
completing the AE form provided in the eCRF. Once the AE is selected as a SAE and the form is 
saved in the eCRF, an email notification will be sent automatically to the Sponsor’s 
Pharmacovigilance department. If for any reason the eCRF is not available, as a backup option, 
the SAE can be declared by email at SafetyReporting@SyneosHealth.com using the paper “SAE 
report form”. 
If for any reason, the eCRF and email are not available, the paper “SAE report form” can be sent 
by fax to +1-877-464-7787 with the provided fax cover page entitled “Serious Adverse Event 
Report transmittal form”. 
Email and fax reporting should be followed by the completion of the AE form in the eCRF as soon 
as possible. 
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The processes are fully described in separate guidelines and will be provided to Investigators with 
the protocol. 
 
9.3.1. 
Follow-up of Serious Adverse Events  
All SAEs, regardless of severity, must be followed up: 
• 
To resolution (the participant’s health has returned to the baseline status or all variables 
have returned to normal), 
or 
• 
Until stabilization of the event has occurred (the Investigator does not expect any further 
improvement or worsening of the event), 
or 
• 
Until the event is otherwise explained regardless of whether the participant is still 
participating in the study. 
Some events, such as metastases, are often ongoing; however, once these events have been 
determined by the Investigator to be stable or chronic, he/she may consider the event to be 
resolved or resolved with sequelae. 
The Investigator will notify the Sponsor of any follow-up information in the eCRF page within 24 
hours of new information awareness. 
Any AEs that are unresolved at the participant’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF. 
Sponsor or designee retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
 
9.3.2. 
Procedure for SAE Communication  
If required by applicable local regulations, the Investigator will promptly notify the relevant IRB/IEC 
(in addition to the Sponsor) of any SAE (including post-study SAEs and follow-up information) that 
occurred at their site or was brought to their attention by the Sponsor. The Investigator will verify 
that the IRB/IEC acknowledges receipt of the notification. 
In case of Suspected Unexpected Serious Adverse Reaction (SUSAR), unusual increase in the 
frequency of the severity of expected SAEs or new safety data which could have an impact on the 
overall expectedness of Serious Adverse Reaction or change in the safety profile of the study 
treatment(s) that require the informed consent to be updated, the Sponsor will prepare a safety 
report according to regulatory requirements relating to safety reporting. 
This report will be communicated by the Sponsor to all Investigators involved in clinical studies 
with xevinapant. 
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9.4. 
Other Events Requiring Immediate Reporting  
9.4.1. 
Overdose  
For this study, an overdose is defined as follows: 
• 
For xevinapant: any dose higher than 200 mg/day. 
• 
For cisplatin: any dose higher than 100mg/m2 per cycle. 
• 
For carboplatin: any dose higher than AUC = 5 per cycle. 
Appropriate supportive treatment should be provided if clinically indicated. In the event of 
overdose, the participant should be observed closely for signs of toxicity. Overdoses should be 
recorded as an AE. 
Any AEs associated with an overdose should be recorded as separate AEs in addition of the AE 
“Overdose”. 
If an overdose on a Merck KGaA, Darmstadt, Germany investigational product (Debio-1143 or 
matched placebo) occurs during the course of the study, the Investigator or other site personnel 
must inform appropriate Sponsor representatives immediately and no later than 24 hours after 
becoming aware of the event. 
The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is provided to the Sponsor’s participant safety data entry site. 
For overdoses associated with an SAE, the standard SAE reporting timelines apply. 
For other overdoses, reporting must occur within 30 days. 
 
9.4.2. 
Pregnancy  
All pregnancies occurring from signing informed consent until 9-months visit should be reported 
to Merck KGaA, Darmstadt, Germany. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the study 
treatment may have interfered with the effectiveness of a contraceptive method. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. 
Elective abortions without complications should not be handled as AEs. 
Pregnancies should be followed up until the final outcome and documented event if the participant 
was discontinued from the study. 
If any pregnancy occurs, the Investigator must: 
• 
Discontinue study treatments (i.e., xevinapant/matched placebo, cisplatin/carboplatin and 
IMRT). 
• 
Complete the pregnancy report form and send it within 24 hours of awareness by email at 
SafetyReporting@SyneosHealth.com or by fax to +1-877-464-7787. 
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For the follow-up information, an updated pregnancy report form should be sent within 24 hours 
in the same way as the initial notification. 
Any serious outcomes experienced by the parent and/or the fetus/child should be reported as 
SAEs using the SAE report form. 
This procedure applies to pregnancies in female participants as well to those in female partners 
of male participants. Information on the pregnancy of a participant’s partner must be obtained 
directly from the participant’s partner. Therefore, prior to obtaining information about the 
pregnancy, the Investigator must obtain the consent of the participant’s partner. 
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10. 
STATISTICAL CONSIDERATIONS  
This section describes the statistical analyses and associated procedures intended to be 
performed during the analysis of the data collected during this clinical study. A detailed description 
of the statistical analyses will be provided in the statistical analysis plan. 
The key elements of the statistical analysis plan are summarized in Table 10-1. A comprehensive 
description is provided in Section 10.4. 
 
Table 10-1 Summary of Statistical Analysis Plan  
Study Design Overview 
This is a prospective, randomized, double-blind, placebo-controlled, multicenter, 
two-arm, parallel-group Phase 3 study comparing the efficacy and safety of 
xevinapant versus matched placebo, when administered in combination with 
platinum-based standard fractionation IMRT in previously untreated LA-SCCHN 
patients suitable for definitive CRT. 
Treatment Assignment 
Eligible participants will be randomized in a 1:1 ratio to receive xevinapant + CRT 
(Arm A) or matched placebo + CRT (Arm B) using dynamic allocation with complete 
randomization. Stratification factors are described in Section 6.3. 
Analysis Sets 
The following analysis sets will be used for planned analyses: Intent-to-treat, Safety, 
 analysis set. 
Please refer to Section 10.3 for the description of the analysis sets. 
Primary Endpoint/Hypothesis 
Xevinapant prolongs EFS as assessed by the BIRC in previously untreated patients 
with LA-SCCHN suitable to receive CRT compared to matched placebo when 
administered in combination with platinum-based standard fractionation IMRT. 
Statistical Methods for Key Efficacy 
Analyses 
The hypothesis on EFS will be evaluated by comparing xevinapant to placebo in 
combination with CRT using a stratified log-rank test. The stratification factors are 
tumor size (T4 vs other) and lymph node involvement (N0-1 vs N2 vs N3). The 
hazard ratio will be estimated using a Cox-proportional hazard regression model 
adjusted for randomization stratification factors. Treatment effect on other time-to-
event endpoints will be estimated using Cox regression model adjusted for 
randomization stratification factors. 
Estimation of the treatment effect on binary endpoints will be done using a logistic 
model adjusted for randomization stratification factors. 
Please refer to Section 10.4.2 and Section 10.4.3 for the detailed description of the 
efficacy analyses. 
Statistical Methods for Key Safety 
Analysis 
Only descriptive statistics will be provided for safety endpoints. Please refer to 
Section 10.4.4. 
 
 
 
 
 
 
 
 
 
 
 
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Multiplicity 
Hierarchical fixed sequence testing procedure is applied to control the type I error for 
the interim analyses and multiple hypotheses testing. The overall type I error is 
controlled at 0.025 one-sided). Please refer to Section 10.4.3 for the hierarchical 
fixed sequence procedure. 
An O'Brien & Fleming type α spending is used for the calculation of the significance 
levels and efficacy boundaries (p-value scale, see Section 10.4.7). 
Sample Size and Power 
With 429 EFS events, the clinical study has about 90% power to detect the expected 
hazard ratio benefit. Please refer to Section 10.2 for full description of the sample 
size determination. 
Abbreviations: BIRC: Blinded Independent Review Committee; CRT: chemoradiotherapy; EFS: event-free survival; 
 
IDMC, Independent Data Monitoring Committee; IMRT, intensity-modulated radiotherapy; LA-SCCHN: 
locally advanced squamous cell carcinoma of the head and neck; OS: overall survival; PA: primary analysis. 
 
10.1. Statistical Hypotheses  
10.1.1. 
Primary Hypothesis  
Xevinapant prolongs EFS as assessed by the BIRC in previously untreated LA-SCCHN patients 
compared to matched placebo when administered in combination with platinum-based standard 
fractionation IMRT. 
 
10.1.2. 
Secondary Efficacy Hypothesis  
Secondary efficacy testing will be done with a hierarchical procedure for the following secondary 
endpoint. It is hypothesized that: 
• 
Xevinapant + CRT prolongs OS compared to placebo + CRT. 
Other efficacy endpoints will be analyzed without any type I error adjustment. 
 
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10.2. Sample Size Determination  
Sample size calculation and evaluation of robustness was perform using R version 3.6.1 and R 
package ‘rpact’ version 2.0.4. as well as EAST 6.5.1.  
 
10.2.1. 
Sample Size  
The sample size was calculated considering the primary endpoint (blinded independent-assessed 
EFS) and interim analyses. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
It is anticipated that 700 participants will be randomized overall (~1000 participants screened). 
Note: After global recruitment reaches the planned sample size for the ITT population (n=700), a 
Chinese extension cohort will be opened to reach randomization of approximately 106 Chinese 
participants from China Mainland (see Section 13.9 for further details). 
 
 
 
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Justification of the assumptions: 
Following the review of the literature (Table 10-2) and considering the variations in populations, 
treatment regimen-dose modulations, endpoint definitions and natural variation, it is expected 
that the Placebo + CRT group (Arm B) will experience a median time to EFS of about 17 
months, leading to an exponential parameter λ of 0.041. 
Table 10-2 Published studies used for the sample size assumptions  
Reference 
Population 
Number of 
participants 
Regimen 
mPFS (months) 
(Hitt et al. 2014)  
Locally advanced 
inoperable 
155 
TPF-CCRT 
14.6 
156 
PF-CCRT 
14.3 
128 
CCRT 
13.8 
(Posner et al. 
2007) 
Nonmetastatic, 
histologically proven 
stage III or IV 
squamous cell 
carcinoma of the oral 
cavity, larynx, 
oropharynx, or 
hypopharynx 
255 
TPF CCRT 
15 
246 
PF CCRT 
10 
(Bonner et al. 
2006) 
LA-SCCHN, stage III 
or IV; including HPV 
positive OPC 
211 
Cetuximab-RT 
17.1 
213 
RT 
12.5 
(Geoffrois et al. 
2018) 
Patients with bulky 
nodal spread—N2b 
or N2c to N3 
179 
Carboplatin+5FU + RT 
12.5 
151 
TPF+cetuximab+RT 
11.5 
(Tao et al. 2018) 
Patients with N0-2b, 
non-operated, stage 
III or IV 
(nonmetastatic) 
LA-SCCHN 
(including oral cavity, 
HPV-positive OPC) 
204 
CT-cetuximab-RT 
37.9 
201 
Cetuximab-RT 
22.4 
 
Abbreviations: 5FU: 5-fluorouracil; CT: chemotherapy; HPV: Human Papilloma Virus; LA-SCCHN: Locally Advanced 
Squamous Cell Carcinoma of the Head and Neck; mPFS: median progression-free survival; OPC: Oropharyngeal 
cancer; PF-CCRT: cisplatin and 5-fluorouracil -concurrent chemoradiation; RT: radiotherapy; TPF-CCRT: docetaxel 
(Taxotere), cisplatin and 5-fluorouracil - concurrent chemoradiation. 
 
The Debio 1143-201 Part B Phase 2 study showed promising results (PFS improvement 
corresponding to a HR=0.37). These results together with a literature review were used to 
determine the EFS treatment effect assumptions. Thus, we expect that the addition of xevinapant 
to CRT will lead to a treatment effect 
, corresponding to a difference of at least 
 
in the prolongation of median EFS in the xevinapant + CRT group (Arm A) (median time estimate 
of
 and exponential parameter 
) as compared with Placebo + CRT group. 
This improvement in outcome is considered clinically relevant and is consistent with published 
data (Bonner et al. 2006); (Blanchard et al. 2011). 
 
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10.2.2. 
Robustness of Sample Size  
10.2.2.1. 
Robustness of Sample Size for Event-free Survival  
Table 10-3 presents the expected power according to alternative hazard ratios while interim and 
primary analyses are triggered using assumptions from Section 10.2.1. In a situation where the 
hazard ratio is smaller than expected, the power at the first interim analysis provides good 
characteristics. In a situation where the hazard ratio is larger than expected, the power is at an 
appropriate level at primary analysis. 
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10.2.2.2. 
Robustness of sample size for overall survival  
Table 10-4 presents the number of events, expected timing of analyses and the power according 
to alternative hazard ratios (expected median OS in control at 
 and annual lost to follow-
up/dropout rate for OS at 
).  
10.2.3. 
Sample Size for PK  
PK blood samples will be collected from all randomized participants, ensuring sufficient collection 
of PK data to perform PK analyses and subsequent exposure/response analyses. 
 
10.3. Analysis Populations  
The following analysis sets will be used for the planned analysis of the global study population: 
Intent-to-treat (ITT): The ITT set will include all randomized participants. Participants will be 
analyzed according to the randomized treatment assignment following the intention-to-treat 
principle. The ITT set will be the primary set for all efficacy and HRQL variables. 
Safety (SAF): The SAF set will include all participants who received at least one dose of study 
medication. Participants will be analyzed according to the actual treatment received. The SAF will 
be used for all safety analyses. 
Pharmacokinetics (PK): The PK set will include all the participants who have undergone at least 
one PK sample scheduled. The PK set will be used for all PK analyses. 
 
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10.4. Statistical Analyses  
10.4.1. 
General Approach  
Time-to-event data will be summarized based on Kaplan-Meier estimates, including but not limited 
to frequency and percentage at risk/censored, median, 1st and 3rd quartile, rate at predefined 
timepoints. Other continuous data will be described using descriptive statistics, including but not 
limited to the number of non-missing values (n), mean, standard deviation, median, minimum and 
maximum value. Categorical data will be described using the participant count and percentage in 
each category (including one for missing data). 
Unless otherwise specified, all inferential tests will be one-sided. Type I error for primary objective 
null hypothesis is preserved at 0.025 one-sided using a group sequential design (O'Brien & 
Fleming type α spending). 
Primary and selected secondary efficacy objectives will be evaluated in a hierarchical fixed 
sequence testing procedure (also called fixed sequence statistical strategy tests). Tests on the 
endpoints will be done in the predefined order specified in Section 10.1.2, all at the same 
significance level α, moving to the subsequent endpoint only after a success on the previous 
endpoint. Such a test procedure will preserve the overall type I error at 0.025 one-sided. 
 
10.4.2. 
Analysis of the Primary Efficacy Endpoint  
This section describes the statistical methods for the analysis of the primary endpoint. 
The primary endpoint is EFS as assessed by the BIRC. Please refer to Section 3 for the definition 
of the primary endpoint and Section 11.2.4 for information on the BIRC. Supportive analysis will 
be done on EFS as assessed by Investigator. 
Censoring rules for the primary and sensitivity analyses of EFS are described in Table 10-5. If a 
participant is meeting a multiple censoring situation, the earliest censoring criterion will be applied. 
Primary treatment failure is defined as requirement of radical salvage surgery before achieving 
a CR that includes the primary tumor site, with documented viable tumor presenting 
anatomopathological findings even in the absence of formal RECIST v1.1 radiological 
progression, occurring up to EOT visit. 
In the situation of a primary treatment failure, a participant will be considered to have an event 
(EFS) at the date of randomization (Michiels et al. 2009). This event can only occur during the 
treatment period. This rule aims to correct for potential bias in the follow-up schedules for tumor 
assessment during treatment (Michiels et al. 2009). 
Table 10-5 Censoring rules for EFS  
Situation 
Primary 
Sensitivity #1 
Sensitivity #2 
No evaluable baseline or post-
baseline assessment*  
Right censored at the date of 
randomization 
Right censored at the date of 
randomization 
Right censored at the date of 
randomization 
Death, PD or any event 
entering in the definition of 
EFS after 2 or more 
Right censored at last 
adequate assessment before 
the consecutive 
Right censored at last 
adequate assessment before 
the consecutive 
Not applicable 
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Situation 
Primary 
Sensitivity #1 
Sensitivity #2 
consecutive missing or 
inadequate tumor 
assessments 
missing/inadequate 
assessments 
missing/inadequate 
assessments 
Initiation of a new anticancer 
treatment for the disease 
under investigation before any 
event entering in the definition 
of EFS 
Right censored at their last 
adequate assessment before 
the initiation of the new 
anticancer treatment 
Not applicable 
Not applicable 
No death, PD, nor any event 
entering in the definition of 
EFS 
Right censored at the date of 
their last adequate 
assessment 
Right censored at the date of 
their last adequate 
assessment 
Right censored at the date of 
their last adequate 
assessment 
Abbreviations: EFS: Event-free survival; PD: Progressive disease 
*An EFS event of any type is considered as a post-baseline assessment. 
 
The Kaplan-Meier method will be used to estimate the EFS curve in each treatment group, see 
Section 10.4.1. Summary statistics, not limited to median, 1st and 3rd quartile, rate at 9, 12, 18, 24, 
30 and 36 months after randomization, will be extracted from the Kaplan-Meier estimates. 
The primary efficacy analysis will assess the difference in EFS between treatment arms using a 
one-sided stratified log-rank test at the α level of 0.025. The stratification factors are tumor size 
(T4 vs other) and lymph node involvement (N0-1 vs N2 vs N3). These factors were chosen among 
the randomization factors to avoid issues caused by very small sample stratum sizes. A Cox-
proportional hazard regression model adjusted for the randomization factors will be used on the 
EFS with primary censoring rule to derive the hazard ratio and 95% CI between the 2 randomized 
regimens. Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model. The stratification factors used for the randomization of participants will be inserted as 
covariates in the regression model. EFS with sensitivity censoring rules will be analyzed with the 
same approach. 
10.4.3. 
Analysis of the Secondary Efficacy Endpoints  
This section describes the statistical methods for the analysis of the secondary efficacy endpoints. 
Selected secondary efficacy endpoints will be evaluated in a hierarchical fixed sequence testing 
procedure (see Section 10.1.2 and Section 10.4.1). 
10.4.3.1. 
Overall Survival  
OS is defined as the time from randomization to death due to any cause. Participants without 
documented death at the time of analysis will be censored at the date of last known contact. 
Kaplan-Meier method will be used to estimate the OS curve in each treatment group. Summary 
statistics, not limited to median, 1st and 3rd quartile, rate at 12, 24, 36, 48 and 60 months after 
randomization, will be extracted from the Kaplan-Meier estimates. 
The treatment difference in OS will be assessed using a one-sided stratified log-rank test at the 
α level of 0.025 using tumor size (T4 and other) and lymph node involvement (N0-1 vs N2 vs N3). 
A Cox-proportional hazard regression model adjusted for the randomization stratification factors 
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will be used on the OS to derive the hazard ratio and 95% CI between the 2 randomized regimens. 
Ties will be handled by replacing the proportional hazards model by the discrete logistic model.  
 
10.4.3.2. 
Progression-free Survival  
Please refer to Section 3 for the definition of PFS as assessed by the BIRC. Supportive analysis 
will be done on PFS as assessed by Investigator. 
Censoring rules for the primary and sensitivity analyses for PFS are described in Table 10-6. 
 
Table 10-6 Censoring rules for progression-free survival  
Situation 
Primary  
Sensitivity #1 
Sensitivity #2 
No evaluable baseline or post-
baseline assessment* 
Right censored at the date of 
randomization 
Right censored at the date of 
randomization 
Right censored at the date of 
randomization 
Death, PD or any event 
entering in the definition of 
PFS after 2 or more 
consecutive missing or 
inadequate tumor 
assessments 
Right censored at last 
adequate assessment before 
the consecutive 
missing/inadequate 
assessments 
Right censored at last 
adequate assessment before 
the consecutive 
missing/inadequate 
assessments 
Not applicable 
Initiation of a new anticancer 
treatment for the disease 
under investigation before any 
event entering in the definition 
of PFS 
Right censored at their last 
adequate assessment before 
the initiation of the new 
anticancer treatment 
Not applicable 
Not applicable 
No death, PD, nor any event 
entering in the definition of 
PFS 
Right censored at the date of 
their last adequate 
assessment 
Right censored at the date of 
their last adequate 
assessment 
Right censored at the date of 
their last adequate 
assessment 
Abbreviations: PD: Progressive disease; PFS: Progression-free survival. 
*Any PFS event is considered as a post-baseline assessment.' 
 
Summary statistics and analysis of PFS will be performed using the same methods as for EFS, 
described in Section 10.4.2. 
 
10.4.3.3. 
Locoregional Control  
Please refer to Section 3 for the definition of LRC as assessed by Investigator. LRC will be 
investigated by BIRC as supportive analysis. 
Censoring rules for the primary and sensitivity analyses for LRC are described in Table 10-7. 
 
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Table 10-7 Censoring rules for locoregional control  
Situation 
Primary  
Sensitivity #1 
Sensitivity #2 
No evaluable baseline or post-
baseline assessment 
Right censored at the date of 
randomization 
Right censored at the date of 
randomization 
Right censored at the date of 
randomization 
PD after 2 or more 
consecutive missing or 
inadequate tumor 
assessments 
Right censored at last 
adequate assessment before 
the consecutive 
missing/inadequate 
assessments 
Right censored at last 
adequate assessment before 
the consecutive 
missing/inadequate 
assessments 
Not applicable 
Initiation of a new anticancer 
treatment for the disease 
under investigation before any 
documented progressive 
disease 
Right censored at their last 
adequate assessment before 
the initiation of the new 
anticancer treatment 
Not applicable 
Not applicable 
No locoregional failure 
Right censored at the date of 
their last adequate 
assessment 
Right censored at the date of 
their last adequate 
assessment 
Right censored at the date of 
their last adequate 
assessment 
Abbreviations: PD: Progressive disease 
 
Summary statistics and analysis of LRC will be performed using the same methods as for EFS, 
described in Section 10.4.2. 
 
10.4.3.4. 
Duration of Response  
Please refer to Section 3 for the definition of DoR as assessed by the BIRC. Supportive analysis 
will be done on DoR as assessed by the Investigator. Participants with non-measurable disease 
only participants having best overall response at non-CR/non-PD will be imputed to non-
responders. 
Primary and sensitivity censoring rules for DoR following the same as those applied to PFS, 
described in Table 10-6. 
Summary statistics and analysis of DoR will be performed using the same methods as for EFS, 
described in Section 10.4.2. 
10.4.3.5. 
Complete Response Rate  
For the computation of CRR, best overall response will be imputed to non-responder for 
participants without evaluable assessment. 
Primary analysis for CRR will be based on the BIRC evaluation of response according to RECIST 
v1.1. Supportive analysis for CRR will be based on Investigator evaluation of response. 
Summary statistics will be provided for CRR at 9 and 12-months post-randomization. CRR and 
CR status at 9 and 12-months post-randomization will be analyzed using a logistic regression. 
The same stratification factors used for the randomization will be applied to the analysis. 
 
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10.4.3.6. 
Overall Response Rate  
For the computation of ORR, best overall response will be imputed to non-responders for: 
• 
participants without evaluable assessment. 
• 
non-measurable disease only participants with best overall response at non-CR/non-PD. 
Primary analysis for ORR will be based on the BIRC evaluation of response according to RECIST 
v1.1. Supportive analysis for ORR will be based on Investigator evaluation of response. 
Summary statistics will be provided for ORR status at 9 and 12-months post-randomization. ORR 
and objective response status at 9 and 12-months post-randomization will be analyzed using a 
logistic regression. The same stratification factors used for the randomization will be applied to 
the analysis. 
10.4.3.7. 
Proportion of Participants with Radical Salvage Surgery  
Participants experiencing END, without anatomopathological evidence of residual malignant cells 
will be imputed as not having experience a radical savage surgery for the computation of the 
proportion of participants with radical salvage surgery. If the number of events permits, time to 
radical salvage surgery will be analyzed using time-to-event techniques. 
Summary statistics will be provided for the proportion of participants with radical salvage surgery 
experienced before 9, 12, 24, 36, 48 and 60-months post-randomization. In addition, the 
proportions will be analyzed using a logistic regression. The same stratification factors used for 
the randomization will be applied to the analysis. 
10.4.3.8. 
Time to Subsequent Systemic Cancer Treatment  
Time to subsequent systemic cancer treatment will be computed as the time from randomization 
to first subsequent systemic cancer treatment for SCCHN. Participant without documented 
subsequent systemic cancer treatment for this disease will be censored at the date of last known 
contact with evidence of no new systemic cancer treatment. 
The Kaplan-Meier method will be used to estimate the time to subsequent systemic cancer 
treatment curve in each treatment group. Summary statistics, not limited to median, 1st and 3rd 
quartile, rate at 12, 18, 24, 36, 48 and 60 months after randomization, will be extracted from the 
Kaplan-Meier estimates. 
The treatment difference in time to subsequent systemic cancer treatment will be assessed by 
using a one-sided stratified (T size and lymph node involvement) log-rank test at the α level of 
0.025. A Cox-proportional hazard regression model adjusted for randomization stratification 
factors will be used to derive the hazard ratio and 95% confidence intervals between the 
2 randomized regimens. Ties will be handled by replacing the proportional hazards model by the 
discrete logistic model 
 
10.4.3.9. 
HRQL Assessment  
For both EORTC QLQ-C30 and EORTC QLQ-HN35 questionnaires, data will be scored according 
to the algorithm described in the EORTC scoring manual (Fayers 2001). 
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Detailed descriptions of the analyses are reported in the statistical analysis plan. 
 
10.4.4. 
Safety Analyses  
Safety, tolerability, and extent of exposure will be assessed through summary information on AE, 
laboratory parameters, vital signs and dosing information. 
 
10.4.4.1. 
Adverse Events  
AE will be coded using Medical Dictionary for Regulatory Activities (MedDRA) dictionary version 
22.1 or higher. 
A treatment-emergent AE is any new sign or symptom, disease, other untoward medical event, or 
change of an existing condition in a participant that begins during or after the first study treatment 
(xevinapant, cisplatin or IMRT) and up to 30 days after treatment end date, whether or not 
considered to be drug-related. Further details will be provided in the statistical analysis plan. 
Incidence (count and percentage) of TEAEs, TEAEs related to study treatments, dose-modifying 
TEAEs, TEAEs leading to treatment discontinuation, TEAEs leading to death, AESIs and SAEs 
will be tabulated and listed by grade group (overall and grade 3 or more) and arm, and by MedDRA 
system organ class and preferred term. Data will be presented overall, for AEs (up to EOT visit), 
SAEs (up to EOS), AESIs during treatment (up to EOT) and late onset AESIs (from EOT to EOS). 
Grade will be based on NCI-CTCAE v5.0. Incidence of participants with treatment interruptions, 
delays, and dose reductions will be tabulated, and treatment compliance will be presented as 
descriptive statistics by arm (overall and per cycle as appropriate). All on-study deaths and 
reasons will be listed. 
 
10.4.4.2. 
Laboratory Parameters  
Safety laboratory parameters worst grades as per NCI-CTCAE v5.0, during treatment until EOT, 
and corresponding changes from baseline will be presented as descriptive statistics by arm and 
by timepoint. Worst post-baseline shift tables will be presented by arm. 
 
10.4.4.3. 
Vital Signs Parameters  
Vital parameters, weight, and ECOG performance status and corresponding changes from 
baseline will be presented as descriptive statistics by arm and by timepoint. 
 
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10.4.4.4. 
Extent of Exposure  
The exposure to xevinapant or matched placebo, chemotherapy and IMRT will be summarized by 
cycle and overall, up to EOT. 
 
 
10.4.6. 
Baseline Descriptive Statistics  
Demographics and baseline characteristics will be assessed and summarized by arm in the ITT 
and safety sets using summary tables and figures. No statistical hypothesis will be performed on 
these baseline characteristics. 
 
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10.4.8. 
Subgroup Analyses  
Treatment effect and associated 95% CI for the primary endpoint and secondary efficacy 
endpoints (PFS, LRC, DoR, CRR, OS, etc.) will be estimated and plotted within each category of 
the following subgroups: 
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• 
Region: North America vs Western Europe vs Rest of the World. 
• 
Primary tumor site: larynx vs other. 
• 
Lymph node involvement: (N0-1 vs N2 vs N3). 
• 
T size: T4 vs other. 
Additional subgroup analysis will be specified in the statistical analysis plan. 
 
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11. 
ETHICAL, REGULATORY AND OPERATIONAL CONSIDERATIONS  
11.1. Ethics  
11.1.1. 
Informed Consent Process  
The Investigator, or a person designated by the Investigator, will obtain written informed consent 
from each participant or their legally authorized representative before any study-specific activity is 
performed. The informed consent process must be documented (see below). 
Each participant will be given oral and written information in an easily understandable language 
describing the nature and duration of the study. 
If required by local regulations, an independent doctor who is not involved in conducting the study 
will be available for potential study participants to consult for information and advice. 
The ICF will clearly state and inform the participants that there is a possibility that xevinapant in 
combination with chemoradiation is an experimental treatment which may not improve their 
condition. The potential side effects and risks, monitoring requirements will also be highlighted. 
The informed consent process must take place under conditions where the participant has 
adequate time to consider the risks associated with study participation. 
The Investigator will retain the original of each participant’s signed consent document. A copy of 
the signed ICF (or original of the ICF, if 2 originals are required to be signed as per local 
regulations) will be provided to the participant or the participant’s legally authorized representative. 
The medical records of participant will include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent was 
obtained. 
Prior to initiation of the study at any site, the study, including the protocol and other study 
documents must be approved by an appropriate IEC or IRB and Regulatory Agencies. Any 
amendment to the protocol will require review and approval by the IEC/IRB before the changes 
are implemented in the study. Amendments classified as “substantial” will also require prior 
approval by Regulatory Agencies before implementation. 
The study must be approved before any participant is requested to sign the ICF. The ICF will be 
approved by an appropriate IEC/IRB and Regulatory Agencies, where required by local 
regulations, and any change to its content will require approval before implementation. In case of 
ICF amendment, a determination will be made regarding whether a new consent needs to be 
obtained from participants who initially provided consent based on a previous version of the ICF. 
 
11.1.2. 
Independent Ethics Committees and Institutional Review Boards  
The Clinical Study Protocol and Amendments to the protocol must be approved by the IRBs/IECs 
before implementation at the sites. 
A letter documenting IEC/IRB approval (in which the protocol title and protocol number are 
specifically identified) and a list of IEC/IRB members (if available) and affiliations should be 
obtained by the Sponsor prior to initiation of the study. 
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Within 90 days of completion of the study (last participant, last visit) or 15 days of early termination 
of the study, the IEC/IRB will be informed of the end of the study by the Investigator, Sponsor or 
designee. 
Every serious or unexpected AE that might affect participant safety must be brought to the IEC’s 
or IRB’s attention by the Investigator if required by relevant IEC/IRB regulations. 
 
11.2. Study Governance and Study Committees  
The study Sponsor are Affiliates of Merck KGaA, Darmstadt, Germany as listed on the title page. 
IECs and IRBs are described in Section 11.1.2. 
 
11.2.1. 
Independent Data Monitoring Committee / Firewall Team 
An IDMC will be established before the randomization of the first participant to provide safety and 
efficacy oversight during the study. The review of safety and efficacy data will be performed 
according to an IDMC Charter that will be prepared before data collection start. All relevant data 
available from this study will be provided for these reviews. 
The responsibilities of the IDMC include: 
• 
To minimize the exposure of participants to an unsafe therapy or dose. 
• 
To make recommendations for changes in study processes where appropriate. 
• 
To advise on the need for dose adjustments because of safety issues. 
• 
To endorse continuation of the study. 
It will also be the responsibility of the IDMC to review the efficacy results at the interim analysis. 
At any time during the study when the IDMC recommends major changes, these 
recommendations will be presented to the TSC (see Section 11.2.3). 
Further details on the membership, responsibilities and working procedures of the IDMC are 
described in the IDMC Charter, provided as a separate document in the study file. 
The Firewall Team will be comprised of relevant Sponsor senior experts (as described in a 
dedicated Firewall Charter), who are independent of the study team, to review the IDMC 
recommendation(s) following interim efficacy analyses with regards to the conduct of the study 
and according to the respective charters, preserving study integrity. 
 
11.2.2. 
Quality Assurance Review Center  
Two RT-QA Review Centers, one for the US sites and one for the rest of the world have been 
identified. 
The responsibilities of the RT-QA Review Center include: 
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• 
To review and approve IMRT plan(s) before starting the first fraction administration to 
ensure IMRT requirements compliance. 
• 
To approve the dosimetry planning before IMRT start. 
• 
To confirm IMRT treatment delivery as per the approved planning and evaluate any 
critical/major deviations from the submitted plan. 
A Radiation Therapy Quality Assurance Manual describing the IMRT plan and the roles and 
responsibilities of the RT-QA Review Center will be available prior to the initiation of the study. 
 
11.2.3. 
Trial Steering Committee  
The Trial Steering Committee (TSC) is a multidisciplinary group of Investigators that, collectively, 
have experience/expertise in the management of participants with condition(s) relevant to study 
and anticipated adverse effects, and in the conduct and monitoring of randomized clinical studies. 
The TSC will also include representatives of the Sponsor. The TSC will ensure transparent 
management of the study according to the protocol as initially written and through decisions made 
based on the IDMC recommendations. Details on the membership and responsibilities of the TSC 
are described in the TSC charter. 
In particular, the TSC will be mainly responsible for: 
• 
Periodic review of the progress of the study. 
• 
Determining if amendments to the protocol or changes to study conduct are required.  
• 
Monitoring the overall conduct of the study, ensuring that it follows the standards set out 
in the GCP guidelines. 
• 
Reviewing the recommendations of the IDMC and/or other study committees and 
suggesting appropriate action to the Sponsor. 
• 
Monitoring the progress of study and deciding on appropriate action in order to maximize 
the chances of completing it within the agreed timelines. 
 
Additional responsibilities include but are not limited to: 
• 
Approving proposed protocol amendments. 
Details on the membership and responsibilities of the TSC are described in the TSC charter. 
 
11.2.4. 
Blinded Independent Review Committee  
The BIRC will perform a blinded central review of clinical and pathological assessments and 
radiological imaging of all participants, as per RECIST v1.1. It will be composed of blinded 
independent reviewers, including radiologists acting as primary reviewers and as adjudicators, 
and oncologists. 
 
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11.3. Data Collection and Quality Assurance  
11.3.1. 
Clinical Monitoring  
At mutually convenient times during the study and after study completion, the Investigator will let 
Sponsor representatives periodically review the eCRF and corresponding office, hospital, and 
laboratory records (source documents e.g., participant’s medical chart, hospital, clinic, and 
laboratory records.) of each study participant. The eCRFs must be completed by the Investigator 
or authorized person on a regular basis and prior to each monitoring visit. 
Monitoring visits allow the Sponsor to evaluate study progress, verify accuracy and completeness 
of eCRFs, resolve any inconsistencies in the study records, and ensure that all protocol 
requirements, applicable local laws, ICH guidelines, and Investigator obligations are fulfilled. 
If eCRFs require support information, the Sponsor may request copies of participant records or 
other source documents. All necessary steps will then be taken to anonymize these documents 
and protect participant identity. Adherence to local and national laws governing protection of 
participant identity will be ensured. 
Monitoring visits can be conducted on site or remotely. Centralized monitoring may be put in place 
when applicable. Details will be included in the study monitoring plan. 
At timely intervals, and at the closing of the study, all investigational treatments will be accounted 
for and dispensing records made available to the Sponsor or its representative. 
 
11.3.2. 
Future Use of Stored Specimens and Data  
After completion of the analyses, the remaining blood and tissue samples may be stored for up to 
a maximum of 15 years after the end of the study. These samples may be used for a retrospective 
examination of safety laboratory tests, pharmacological effects of xevinapant, metabolic profiling, 
endogenous biomarkers, bioanalytical investigations or to further contribute to the understanding 
of molecular pathways involved in oncogenesis or the biology of cancer. For China, the use of 
remaining samples will be in accordance with local regulation.  
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. 
 
11.3.3. 
Quality Assurance and Quality Control  
11.3.3.1. 
Sponsor Audits  
During the study or after the study has been completed, the Investigator must allow Sponsor 
representatives or external auditors to conduct an audit of the study. The purpose of the audit is 
to evaluate compliance with GCP guidelines, applicable regulations, the study protocol and the 
Sponsor’s procedures, and to assess accuracy of the study data. 
Before the audit, the Investigator will be contacted by the monitor to arrange a convenient time for 
the visit. Investigator and staff are expected to be present, co-operate with the auditors, and allow 
direct access to all participant records supporting the eCRFs, and other study related documents. 
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11.3.3.2. 
Regulatory Agency Inspections  
The Investigator must permit a Regulatory Agency/IEC/IRB inspection during the study or after 
the study has been completed. The purpose of such an inspection is to conduct an official review 
of documents, facilities, records, and any other resources that are deemed by the authority(ies) to 
be related to the clinical study. 
The Investigator and staff are expected to be available for the inspection and allow access to 
participant records supporting the eCRFs and other study related documents. If given advance 
notice of this inspection, the Investigator must contact the Sponsor immediately. 
 
11.3.4. 
Data Handling and Record Keeping  
11.3.4.1. 
Confidentiality and Privacy  
The Investigator will ensure that participant reports and samples are identified only by an identifier 
to maintain participant confidentiality. All participant study records will be kept safely in an access-
controlled area. Identification code lists linking the participant names to identifiers should 
preferably be stored separately from participant records. Clinical information will not be released 
without written permission from the participant, except for monitoring by Regulatory Authorities or 
the Sponsor. 
 
11.3.4.2. 
Data Management and Validation  
Data entry, verification and validation will be captured using an electronic data capture (EDC) 
system. EDC system is a web-based computerized system designed for the collection of clinical 
data in electronic format (eCRF); accessed via an Internet URL link. EDC system access 
(username and password) will be provided upon completion and confirmation of prerequisite 
training. Username and passwords are personal and confidential and must not be shared. 
Validation of the eCRF data is performed by i) automatic EDC system checks and ii) other data 
review tools, such as data review listings. Data validation may result in the generation of queries. 
A query is a request for further information or clarification which may lead to data change. All 
queries (automatic and manual) will be generated and tracked within the EDC system until 
resolution. Manual queries can be raised directly into the EDC system by the clinical study team 
depending on the assigned EDC role throughout the duration of the study. 
A clinical research associate will perform a source data verification on an ongoing basis to ensure 
completeness and consistency of data. 
Data management reviews will be performed on an ongoing basis to ensure completeness and 
consistency of the eCRF data, taking also into account external data. 
A medical review focused on completeness and consistency of clinical safety data will be 
conducted on an ongoing basis. 
 
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11.3.4.3. 
Data Reporting and Electronic Case Report Forms  
The Investigator and/or designee will accurately, completely, and in a timely manner enter data 
resulting from execution of the protocol into eCRFs. One eCRF will be completed for each 
participant and must be electronically signed and dated by the Principal Investigator responsible 
for participant care during the study. The EDC system audit trail captures all eCRF data related 
activities such as: data entry, data modifications, data verification, data lock, e-signature etc. At 
the end of the study, each site will be given an electronic copy of all study data entered in the 
eCRF plus external data. eCRF data will be extracted from the EDC system into SAS® datasets 
on a periodic basis and at defined study timepoints for statistical analysis. 
 
11.3.4.4. 
Study Records Retention  
The Investigator will maintain adequate study records including the CD-ROM with electronically 
collected study data, medical records, laboratory reports, ICFs, drug disposition records, safety 
reports, information regarding participants who discontinued and other pertinent data, such as 
letters and administrative documents exchanged between the Sponsor and the center. Records 
can be in paper or electronic format. 
All study records must be retained by the Investigator for the maximum period of time authorized 
by the hospital, institution or clinic but in no case for less than 15 years after study completion. 
To avoid any possible errors, the Investigator must contact the Sponsor prior to the destruction of 
any study records or if leaving the institution where the study was conducted. The Investigator will 
notify the Sponsor in the event of accidental loss or destruction of any study records. 
 
11.4. Protocol Deviations  
All protocol deviations should be documented. 
 
11.5. Changes in the Conduct of the Study  
See Section 13.9. 
11.5.1. 
Public Health Emergencies  
In case of a public health emergency, such as pandemics, study procedures might have to be 
adapted to enhance safety for participants and study personnel, as well as to accommodate WHO 
and/or local Health Agencies recommendations. 
Such adaptations include, but are not limited to, more restrictive eligibility criteria to temporarily 
exclude participant sub-populations at higher health risk, alternative visit schedules for enrolled 
participants, study monitoring procedures, alternative supply chain to ensure delivery of 
medication to participant on treatment, etc. 
Such changes will be implemented via separate communication to Investigators and captured in 
the trial master file. 
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Unless such changes are to be implemented on a permanent basis for the rest of the study, a 
protocol amendment will not be issued. Communication to the EC/IRBs and Regulatory Agencies 
on implementation of these time-limited changes will follow local requirements. 
 
11.6. Publication and Data Sharing Policy  
Results of this Phase 3 study will not be publicly disseminated or published until the study data 
are mature for the analysis of the primary study endpoint (as defined by the protocol). The 
publications must be conform to the CONSORT guidelines (Schulz et al. 2010). 
However, for the purpose of submission of abstracts to congresses, a draft version of the analysis 
report may be generated if the Sponsor's Statistician determines prior to abstract submission that 
the inconsistencies remaining in the database will not affect the conclusions of the study, and that 
the database can be cleaned and locked in sufficient time to enable the preparation of the final 
statistical report by the time of presentation. In this case, the abstract should clearly stipulate that 
the results are not definitive. 
The publication of the results of ancillary studies (e.g., translational research) is authorized at any 
time provided they do not mention the primary and secondary study endpoints. 
All publications reporting results of this Phase 3 study must be reviewed and approved by the 
Sponsor's Statistician and Medical Monitor in charge of the study, the first author and the TSC. 
The first author is responsible for ensuring that all co-authors have seen and approved the final 
version of the publication prior to submission. A written agreement with the intent to submit a 
publication must be reached between the Sponsor, the first author and the TSC. 
In accordance with the International Committee of Medical Journal Editors (Editors 2010), each 
author of the publication should have participated sufficiently in the work to take public 
responsibility for the content. All other contributors (clinicians, pathologists, etc.) who do not meet 
enough criteria for authorship will be acknowledged in the publication. 
For the primary publication, the first author will be a TSC member who will be the primary person 
responsible for generating the first manuscript draft, followed by the other TSC members. In 
principle, the last author will be a TSC Chairman (if different from the first author). The 
Investigators who enrolled evaluable participants in the study will be included as co-authors up to 
the total number of co-authors allowed by the journal, according to their contribution to participant 
enrolment. 
Coordinators of integrated translational research components of the study or pathologists 
responsible for the central pathology review that is part of the study also qualify as co-authors. 
Two Sponsor representatives will be co-authors. These 2 co-authors are usually the Statistician 
and the Medical Monitor who oversaw and contributed to the study. 
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All Investigators who enrolled evaluable participants into the study (i.e., clinicians) or contributed 
scientifically to the study (i.e., pathologists, collaborators from the same institutions, etc.) will be 
acknowledged in the publication. The acknowledgment list should include the name of all 
participating institutions and the name of the clinicians and other scientists involved with the study 
at that institution. Whenever a study participant has moved from one institution to another in the 
course of the study, that participant is listed with the institution to which he/she was affiliated at 
the time of starting his/her participation to the study, with the mention “(now at new affiliation)”. 
Sponsor staff that made a substantial scientific contribution to the study but are not co-authors 
should be mentioned in the acknowledgment section (i.e., data managers, clinical scientists, 
clinical study managers). 
The person who took the lead in conducting an ancillary study is the first author of the relevant 
publication. The Sponsor representatives who contributed to the design, conception, analysis and 
publication, if any, will also be co-authors. The list of co-authors must be approved by the TSC 
and Sponsor. 
 
11.7. Insurance Policy  
The Sponsor will subscribe a liability insurance covering his and the Investigator’s responsibility 
as well as the responsibility of any person involved in the conduct of the study, provided there is 
proper adherence to the protocol. An insurance certificate will be provided by the Sponsor to the 
IEC/IRB if required. 
 
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13. 
APPENDICES  
 
13.1. ECOG Performance Status  
Table 13-1 ECOG Performance Status  
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 
50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Source: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
13.2. Cisplatin Administration  
Please consult and follow the instructions provided in your local label. 
 
Preparation 
Do not use needles or intravenous sets containing aluminum parts that can come in contact with 
cisplatin for injection during preparation or administration. Aluminum reacts with cisplatin for 
injection, causing precipitate formation and a loss of potency. 
Cisplatin for injection is a cytotoxic drug. Follow applicable special handling and disposable 
procedures.
 
Dilution 
For preparation of the infusion solution, it is recommended that the solution be further diluted in 
1 to 2 L of a compatible infusion solution with or without 37.5 g of mannitol. Refer to detailed 
references for specific infusion solution stability and compatibility information. 
Administration 
Administer cisplatin for injection by slow intravenous infusion. 
 
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Warnings and Precautions 
Nephrotoxicity 
Cisplatin for injection can cause dose-related nephrotoxicity, including acute renal failure that 
becomes more prolonged and severe with repeated courses of the drug. Renal toxicity typically 
begins during the second week after a dose of cisplatin for injection. Patients with baseline renal 
impairment, geriatric patients, patients who are taking other nephrotoxic drugs, or patients who 
are not well hydrated may be more susceptible to nephrotoxicity. 
Ensure adequate hydration before, during, and after cisplatin for injection administration (see 
Appendix 13.3). Measure serum creatinine, blood urea nitrogen, creatinine clearance, and serum 
electrolytes including magnesium prior to initiating therapy, and as clinically indicated. Consider 
magnesium supplementation as clinically needed. 
Creatinine, eGFR and electrolytes local measurement must take place 48 hours (±12 hours) after 
cisplatin administration to avoid or mitigate renal toxicities. 
Peripheral Neuropathy 
Cisplatin for injection can cause dose-related peripheral neuropathy that becomes more severe 
with repeated courses of the drug. Neurologic symptoms have been reported to occur after a 
single dose. Neuropathy can also have a delayed onset from 3 to 8 weeks after the last dose of 
cisplatin for injection. Manifestations include paresthesias in a stocking-glove distribution, 
areflexia, and loss of proprioception and vibratory sensation. The neuropathy may progress further 
even after stopping treatment. Peripheral neuropathy may be irreversible in some patients. 
Consider permanent discontinuation of cisplatin for injection for patients who develop symptomatic 
peripheral neuropathy. Geriatric patients may be more susceptible to peripheral neuropathy. 
Nausea and vomiting 
Cisplatin for injection is a highly emetogenic antineoplastic agent. Premedicate with antiemetic 
agents. Without antiemetic therapy, marked nausea and vomiting occur in almost all patients 
treated with cisplatin for injection and may be so severe that the drug must be discontinued. 
Nausea and vomiting may begin within 1 to 4 hours after treatment and last up to 72 hours. 
Maximal intensity occurs 48 to 72 hours after administration. Various degrees of vomiting, nausea, 
and/or anorexia may persist for up to 1 week after treatment. Delayed nausea and vomiting 
(begins or persists 24 hours or more after chemotherapy) has occurred in patients attaining 
complete emetic control on the day of cisplatin for injection therapy. Consider the use of additional 
antiemetics following infusion. 
Myelosuppression 
Myelosuppression suppression occurs in 25% to 30% of patients treated with cisplatin for injection. 
Fever and infection have been reported in patients with neutropenia. Potential fatalities due to 
infection (secondary to myelosuppression) have been reported. Geriatric patients may be more 
susceptible to myelosuppression. 
Perform standard hematologic tests before initiating cisplatin for injection, before each subsequent 
course, and as clinically indicated. Closely monitor participants for the development of signs and 
symptoms of infection during and after treatment with cisplatin for injection. For participants who 
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develop severe myelosuppression during treatment with cisplatin for injection, consider dose 
modifications and manage according to clinical treatment guidelines. 
Hypersensitivity reactions 
Cisplatin for injection can cause severe hypersensitivity reactions, including anaphylaxis and 
death. Manifestations have included facial edema, wheezing, tachycardia, and hypotension. 
Hypersensitivity reactions have occurred within minutes of administration to patients with prior 
exposure to cisplatin for injection. 
Monitor participants receiving cisplatin for injection for possible hypersensitivity reactions. Ensure 
supportive equipment and medications are available to treat severe hypersensitivity reactions. 
Severe hypersensitivity reactions require immediate discontinuation of cisplatin for injection and 
aggressive therapy. Participants with a history of severe hypersensitivity reactions should not be 
rechallenged with cisplatin for injection. Cross-reactivity between platinum-based antineoplastic 
agents has been reported. Cases of severe hypersensitivity reactions have recurred after 
rechallenging patients with a different platinum agent. 
Ototoxicity 
Cisplatin for injection can cause ototoxicity, which is cumulative and may be severe. Consider 
audiometric and vestibular function monitoring. 
Ototoxicity is manifested by tinnitus, hearing loss in the high-frequency range (4,000 to 8,000 Hz) 
and/or decreased ability to hear normal conversational tones. Ototoxicity can occur during or after 
treatment and can be unilateral or bilateral. Deafness after the initial dose of cisplatin for injection 
has been reported. Vestibular toxicity has also been reported. 
Ototoxic effects can be more severe and detrimental in pediatric patients, particularly in patients 
less than 5 years of age. The prevalence of hearing loss in pediatric patients is estimated to be 
40-60%. Additional risk factors for ototoxicity include simultaneous cranial irradiation, treatment 
with other ototoxic drugs and renal impairment. Consider audiometric and vestibular testing in all 
pediatric patients receiving cisplatin. 
Genetic factors (e.g., variants in the thiopurine S-methyltransferase [TPMT] gene) may also 
contribute to the cisplatin-induced ototoxicity; although this association has not been consistent 
across populations and study designs. 
Ocular toxicity 
Optic neuritis, papilledema, and cortical blindness have been reported in patients receiving 
standard recommended doses of cisplatin for injection. Blurred vision and altered color perception 
have been reported after the use of regimens with higher doses and dose frequencies of cisplatin 
for injection. The altered color perception manifests as a loss of color discrimination, particularly 
in the blue-yellow axis and irregular retinal pigmentation of the macular area on fundoscopic exam. 
Improvement and/or total recovery usually occurs after discontinuing cisplatin for injection but can 
be delayed. 
Secondary malignancies 
The development of acute leukemia secondary to the use of cisplatin for injection has been 
reported. In these reports, cisplatin for injection was generally given in combination with other 
leukemogenic agents. 
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Embryo-fetal toxicity 
Based on human data, cisplatin for injection can cause fetal harm when administered to a pregnant 
woman. Advise pregnant women and females of reproductive potential of the potential risk to a 
fetus. Advise females of reproductive potential to use effective contraception during treatment and 
for 14 months after the last dose of cisplatin for injection. Advise male participants with female 
partners of reproductive potential to use effective contraception during treatment and for 
11 months after the last dose of cisplatin for injection. 
Injection site reactions 
Injection site reactions can occur during the administration of cisplatin for injection. Local soft 
tissue toxicity has been reported following extravasation of cisplatin for injection. Severity of the 
local tissue toxicity appears to be related to the concentration of the cisplatin for injection solution. 
Infusion of solutions with a cisplatin for injection concentration greater than 0.5 mg/mL may result 
in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema. 
Because of the possibility of extravasation, closely monitor the infusion site during drug 
administration. 
 
13.3. Cisplatin Hydration Guidelines   
Adequate hydration must be maintained from 2 to 12 hours prior to administration until minimum 
6 hours after the administration of cisplatin (SmPC TEVA v6.0 2019). 
Hydration is necessary to cause sufficient diuresis during and after treatment with cisplatin. It is 
realized by intravenous infusion of one of the following solutions: 
• 
Sodium chloride solution 0.9% 
• 
Mixture of sodium chloride solution 0.9% and glucose solution 5% (1:1). 
Hydration prior to treatment with cisplatin: 
• 
Intravenous infusion of 100 to 200 ml/hour for a period of 6 to 12 hours, with a total amount 
of at least 1 L. 
Hydration after termination of the administration of cisplatin: 
• 
Intravenous infusion of another 2 liters at a rate of 100 to 200 ml per hour for a period of 6 
to 12 hours. 
Forced diuresis may be required should the urine secretion be less than 100 to 200 ml/hour after 
hydration. Forced diuresis may be realized by intravenously administering 37.5 g mannitol as a 
10% solution (375 ml mannitol solution 10%), or by administration of a diuretic if the kidney 
functions are normal. The administration of mannitol or a diuretic is also required when the 
administrated cisplatin dose is higher than 60 mg/m2 of body surface. 
It is necessary that the participant drinks large quantities of liquids for 24 hours after the cisplatin 
infusion to ensure adequate urine secretion. 
Hydration guidelines may be modified at the discretion of the treating physician provided adequate 
pre and post cisplatin hydration is achieved, and renal function remains adequate. 
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Consider a more extensive hydration regimen under certain circumstances: 
Additional pre hydration with normal saline iv or orally at minimum in the 48 hours preceding 
cisplatin infusion and a more extensive post-hydration regimen is requested whenever possible in 
those patients with risk factors for renal toxicity, e.g., proteinuria, diabetes, and hypertension. 
The patient’s hydration status is requested to be reviewed whenever a patient’s renal lab is 
worsening during the study, with a mandatory review on Day 4. Attention should also be paid to 
any signs of dehydration (insufficient urine outputs) or conditions leading to a potential dehydration 
like diarrhea, vomiting, undernutrition, infection/fever. 
In case of inadequate hydration status and worsening renal lab, additional iv hydration is 
requested whenever possible until renal lab improves. 
 
 
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13.4. HRQL Questionnaires  
13.4.1. 
EORTC QLQ-HN35  
The EORTC QLQ-HN35 is a disease-specific module capturing HRQL dimensions that affect 
patients with head and neck cancer. It is composed of 7 symptom scales (pain, swallowing, 
senses, speech, social eating, social contact, sexuality), 6 symptom items (problems with teeth, 
trismus, xerostomia, sticky saliva, coughing, feeling ill), and 5 dummy (yes/no) items (use of 
painkillers, use of nutritional supplements, use of feeding tube, weight decrease, weight increase), 
for a total of 35 items. Participants’ answers are collected with a one-week recall period. Symptom 
scales and items are presented in 4-point Likert scales. 
Large international samples (N=662) exhibited a high internal reliability (Cronbach’s α > 0.70), 
construct validity (multi-trait scaling analysis ρ≥0.40) and criterion validity (as assessed by group 
comparison method) of the instrument (Bjordal et al. 2000; Sherman et al. 2000). 
The EORTC QLQ-HN35 module has been validated for the different anatomical subsites, multiple 
disease stages, different treatment modalities (i.e., RT, chemotherapy, CRT and surgery) and 
across multiple countries (Bjordal et al. 1999; Bjordal et al. 2000; Singer et al. 2009). Validated 
translations of the EORTC QLQ-HN35 are available in 65 languages, including languages from 
European, Asian and Latin American countries covering target study sites. The instrument is 
meant to be used in conjunction with the EORTC core cancer module (EORTC QLQ-C30). 
A 
specimen 
of 
the 
questionnaire 
(UK 
English) 
is 
available 
at 
https://qol.eortc.org/questionnaire/qlq-hn35/. 
 
13.4.2. 
EORTC QLQ-C30  
The EORTC QLQ-C30 version 3.0 questionnaire captures HRQL dimensions that are common to 
patients with cancer independently of the cancer type by which they are affected. It is composed 
of 5 functional scales (emotional, physical, cognitive, social and role), 3 multi-item scales (fatigue, 
pain, nausea/vomiting) and 6 single-item scales (dyspnea, insomnia, appetite loss, constipation, 
diarrhea, financial difficulties) and one global health scale, for a total of 30 items (Aaronson et al. 
1993). 
Participants’ answers are collected with a one-week recall period and questionnaire items are 
presented in Likert scales (7-point scale for global health status, 4-point scale for all other items). 
The internal reliability and construct validity of the instrument have been tested in large 
international samples of heterogeneous head and neck patients; validated translations of the 
EORTC QLQ-C30 are available for more than one hundred languages (Bjordal et al. 2000). 
For both selected EORTC questionnaires, a score variation of at least 10 points for each item is 
considered clinically meaningful (King 1996; Osoba et al. 1998; Bjordal et al. 2000; Hammerlid et 
al. 2001; Cocks et al. 2011; Cocks et al. 2012). The 10-point threshold of clinical significance has 
been defined across different cancer indications and could be lower in specific cancer types 
(Cocks et al. 2011; Cocks et al. 2012). 
A 
specimen 
of 
the 
questionnaire 
(US 
English) 
is 
available 
at 
https://qol.eortc.org/questionnaire/eortc-qlq-c30/. 
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13.5. Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 Applied 
to this Study in Locally Advanced SCCHN  
The text below was derived from Eisenhauer et al. 2009 and Schwartz et al. 2016. Guidance, 
adjustments and clarification specific to this study in locally advanced SCCHN, and not necessarily 
in the original articles, has been added. 
 
Background and definitions 
Response and progression will be evaluated in this study based on the international criteria 
proposed by the RECIST Working Group (Version 1.1). Unidimensional measurements of tumor 
lesions are used in the RECIST criteria. Individual lesions are either measurable or non-
measurable using the criteria provided below. 
 
Study-permitted imaging modalities and associated procedures 
 
• 
CT, MRI  
CT is the best and most reproducible method currently available to measure lesions selected for 
response assessment. If CT scans have a slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness. MRI is also acceptable in this study, 
except for chest imaging, where CT is mandatory.  
• 
Ultrasound  
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Needle localization images for biopsy site may however be useful. 
• 
Endoscopy, laparoscopy  
The utilization of these techniques alone for objective tumor evaluation is not permitted in this 
study. In this study, biopsy (endoscopic or otherwise) of a suspected new lesion to confirm or 
exclude malignant nature and provide relevant histological information is strongly encouraged 
when clinically feasible. Unbiopsied apparent recurrences visible only on endoscopy are not 
considered sufficient evidence alone to be markers of progression. 
• 
Tumor markers  
Tumor markers for progression are not used in this study. 
• 
Cytology, histology  
In this study, biopsy of a suspected new lesion or residual/recurrent mass to confirm or exclude 
malignant nature and provide histological information relevant to the endpoint is strongly 
encouraged when clinically feasible. 
• 
18F-FDG -PET + CT  
This study incorporates 18F-FDG -PET scanning to complement CT/MRI scans in assessment of 
progression (particularly possible ‘new’ disease.) However, the use of 18F-FDG-PET to upgrade 
response to CR unsupported by biopsy is not applied to this study. 
 
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Assessment methodology 
• 
Assessment methodology of measurable lesions selected for measurement 
Non–nodal tumor lesions must be accurately measured in one dimension, the longest diameter in 
the plane of measurement, with a minimum size of 10 mm by CT scan (irrespective of scanner 
type) and MRI (no less than double the slice thickness and a minimum of 10 mm.) Clinical 
observations, clinical caliper measurements, photographic assessments, and plain radiographs 
are not permitted in this study. All measurements should be recorded in metric notation. 
The short axis of a lymph node, or conjoined mass of nodes, is the longest perpendicular to the 
longest diameter in the axial plane. To be considered pathologically enlarged and measurable at 
baseline, a lymph node must be ≥ 15 mm in short axis when assessed by CT or MRI scan (Scan 
slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the 
short axis of nodes will be measured and followed. 
• 
Assessment methodology of non-measurable disease 
All other lesions (or sites of disease), including small lesions (< 10 mm using spiral CT or MRI 
scan), as well as measurable lesions that are not selected as target lesions, are considered 
non-measurable disease. RECIST criteria define many baseline types of lesion that are always 
non-measurable, but all of these are excluded from this study. Participants with only 
non-measurable disease at baseline but whose overall disease burden is still assessable by 
imaging are considered to have evaluable (non-measurable) disease. 
• 
Assessment of special lesion types 
a) Bone lesions. There will be no malignant bone lesions at baseline in this study due to 
inclusion/exclusion criteria, hence discussion of measurability of bone lesions at baseline 
and of lesions seen at baseline on bone scans is unnecessary. 
b) Cystic lesions. Radiographically defined simple cysts should not be considered as 
malignant lesions. Complex malignant cystic lesions will not occur at baseline in this study 
due to inclusion/exclusion criteria and hence need not be considered further 
c) Lesions with local irradiation: In this study, all lesions seen at baseline will receive 
irradiation as part of the study treatment, and therefore it is impossible to avoid radiation 
impact on assessments. As a result, the processes of selection and following of target 
lesions should not be influenced by past or current irradiation. 
 
Process for evaluation of disease at baseline 
All baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. The same method of assessment and 
the same technique should be used to characterize each identified and reported lesion at baseline 
and during follow-up.  
• 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but also should be those suitable for reproducible repeated measurements. 
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Lymph nodes: Pathological nodes which are defined as measurable and may be identified as 
target lesions at baseline must have a short axis of ≥ 15 mm by CT or MRI scan. Only the short 
axis of these nodes will contribute to the baseline sum of diameters. All other pathological nodes 
(those with short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that 
have a short axis < 10 mm at baseline are considered non-pathological and should not be 
recorded or followed.  
A sum of diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and recorded as the baseline sum of diameters. The baseline sum of 
diameters will be used as reference to further characterize any later objective tumor changes in 
the measurable dimension of the disease.  
• 
Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required, 
except short axis of nodes and then only to confirm or exclude pathological enlargement:  these 
lesions should be followed as ‘present’, ‘absent’, or reported overall as ‘unequivocal progression’. 
Multiple non-target lesions involving the same organ can be a single item on the case record form 
(e.g., ‘multiple liver metastases’).  
 
Process for assessment of disease at each timepoint after baseline 
• 
Evaluation of Target Lesions 
A new sum of diameters for all target lesions will be calculated and recorded as the sum of 
diameters for that timepoint. This timepoint sum of diameters will be used for comparison with 
that at baseline and at the timepoint when the sum of diameters is least (the nadir): the details of 
the outcome of each comparison are shown in Table 1 below. 
 
Table 1 
Response Status Definition for Target Lesions at each Timepoint 
Observed disease 
Response 
Abbreviation 
Disappearance of all target lesions except pathological lymph nodes. Any 
pathological nodes (target or non-target) must have reduction in short axis to 
< 10 mm. 
Complete 
Response 
CR 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum of diameters. 
Partial 
Response 
PR 
At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study or at baseline (the nadir.) In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.   
Progressive 
Disease 
PD 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum of diameters at baseline or on study. 
Stable 
Disease 
SD 
One or more target lesions have not been assessed or assessed using a different 
modality from baseline or nadir, so adequate comparison of the images is impossible. 
Not 
Evaluable 
NE 
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• 
Special points 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded even if the nodes regress to below 10 mm on study. This means that, 
when lymph nodes are included as target lesions, the sum of diameters may not be zero even if 
CR criteria are met. In order to qualify for CR, each node must achieve a short axis < 10 mm. For 
PR, SD, and PD, the actual short axis measurement of the nodes also is to be included in the sum 
of diameters of target lesions. 
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 when very small. However, sometimes the radiologist may not feel 
able to assign an exact measure and may consider them ‘too small to measure’. 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 and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned.  
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Target lesions that are biopsied or excised: On occasion, target lesions may be biopsied or 
excised. Measurements of such lesions may no longer be suitable for accurate assessment of 
response and/or progression. In this situation a sum of diameters including any residual lesion 
should still be calculated, and if the sum of diameters is still increased by 20% over nadir, disease 
progression is diagnosed. If doubt remains, the entire disease burden of the participant should be 
considered and compared with that at baseline as though there was only evaluable, non-
measurable disease at baseline. In such a situation, non-CR/non-PD becomes a possible 
timepoint assessment and even best overall response even though there was measurable disease 
at baseline. To minimize the risk of this eventuality, study imaging before biopsy is advised. 
• 
Evaluation of Non-target Lesions 
While some non-target lesions may actually be measurable, they need not be measured (except 
lymph nodes when pathological nature is uncertain) and instead should be assessed only 
qualitatively, according to the timepoint assessment criteria shown in Table 2 below: 
 
Table 2 
Response Status Definition for Non-target Lesions at each Timepoint 
Observed disease 
Response 
Abbreviation 
Disappearance of all non-target lesions except for lymph nodes. 
All lymph nodes must be non-pathological in size (< 10 mm short 
axis). 
Complete Response 
CR 
Persistence of one or more non-target Lesions. 
Neither complete response 
nor progressive disease 
Non-CR/non-PD 
Unequivocal progression of existing non-target lesions 
Progressive disease 
PD 
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Observed disease 
Response 
Abbreviation 
No non-target lesions seen at baseline 
No non-target lesions 
NA 
Assessment not possible due to inadequate or missing images. 
Not Evaluable 
NE 
 
• 
Special points 
When the participant has both target and non-target lesions. To achieve ‘unequivocal progression’ 
on the basis of the non-target disease, there must be an overall substantial worsening in non-
target disease such that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit new therapy. A modest ‘increase’ in the size of 1 or more 
non-target lesions is insufficient to quality for unequivocal progression status. The designation of 
overall progression solely on the basis of change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare.  
When the participant has only non-target lesions. In this study, it is not a requirement for study 
entry to have measurable disease. The same general concepts apply here as noted above; 
however, in this instance there will be no measured disease assessment to balance the 
interpretation of an increase in non-measurable disease burden. The test that should be applied 
when assessing participants for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is at least comparable in 
magnitude to the increase that would be required to declare PD for measurable disease. 
• 
Evaluation of New Lesions  
The appearance of new malignant lesions denotes disease progression by RECIST v1.1. The 
finding of a new lesion should be unequivocal: i.e., not attributable to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than 
tumor. A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate PD. Exceptionally, since the endpoints of this 
study differentiate between locoregional progression and distant metastasis, it is necessary to 
differentiate between locoregional lesions and metastases elsewhere. Therefore, data on new 
lesions in each of these locations will be required if available. If the first manifestation of disease 
progression is distant metastasis, then assessments for locoregional control should continue if 
possible, and vice versa. Note: As this study is in locally advanced disease, all target and non-
target lesions at baseline will lie within the locoregional volume and therefore no similar 
differentiation at baseline is possible or required. 
If a new lesion is equivocal, either continued therapy and follow-up evaluation or biopsy and 
histological examination will clarify if it represents truly new disease. If repeat scans or biopsy 
confirm a new lesion, then PD should be declared using the date of the initial scan. 
In case histopathological results of a new lesion unequivocally reveal a non-squamous histology 
of the new malignant lesion, this will not be counted as disease progression within the primary or 
secondary endpoints of this study. 
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Evaluation of disease status at each post-baseline timepoint  
For participants with measurable disease, the assessment of response status at each timepoint 
will be an amalgamation of the individual response statuses of target lesions, non-target lesions 
and new lesions, and is shown in Table 3 below. 
Table 3 
Timepoint Assessment of Disease Status by Imaging for Participants with 
Measurable Disease at Baseline.  
Timepoint response in: 
Overall Timepoint 
Response 
Target Lesions 
Non-Target Lesions 
New Lesions 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Any, except PD or NE 
No 
PR 
SD 
Any, except PD or NE 
No 
SD 
Not all measured 
Any, except PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR=complete response, NE=not evaluable, PD=progressive disease, PR=partial response, SD=stable disease.  
 
The RECIST papers referenced in this document provide no similar assessment paradigm for 
response status at timepoint for participants with evaluable but non-measurable disease at 
baseline, but one can be derived from the information above, and it is provided in Table 4 below.   
 
Table 4 Timepoint Assessment of Disease Status by Imaging for Participants with Non-
measurable Disease at Baseline, or due to Biopsy or Excision  
Timepoint response  
Overall Timepoint Response 
Non-Target Lesions 
New lesions 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
NE 
No 
NE 
PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR=complete response, NE=not evaluable, PD=progressive disease.   
 
• 
Special points 
Impact of biopsy and excision. Due to biopsy or excision of target lesions, some participants with 
measurable disease at baseline may have a timepoint response or best overall response of Non-
CR/Non-PD 
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Symptomatic progression. Symptomatic progression alone is not a determinant of disease 
progression in this study. 
Handling equivocal findings of progression. For equivocal findings of progression (e.g., very small 
and uncertain new lesions; cystic changes or necrosis in existing lesions), in the absence of 
histological verification of new malignant lesions, treatment may continue at the investigator’s 
discretion until the next scheduled assessment. If, at the next scheduled assessment, progression 
is definite, the date of progression should be the earlier date when progression was first suspected 
Further information 
Further information on the assessment of disease by imaging in this study is available in the 
training materials, including slide presentations and videos. 
 
 
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13.6. Audiometry Assessment (Specific for investigational sites in France)  
As requested by the French ANSM, an audiometry must be performed at screening, C2D1 and 
C3D1 within 5 days before platinum-based chemotherapy and at any time if clinically indicated as 
per institutional or national guidelines. During the follow-up period, an audiometry is to be 
performed only if clinically indicated, as per institutional or national guidelines. 
 
 
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13.7. Conduct of The Study during the COVID-19 Pandemic (Specific for 
Investigational Sites in Germany)  
Benefit/risk assessment of the conduct of the study during the COVID-19 Pandemic 
Efficacy results from the 36-month analysis of Debio 1143-201B in LA-SCCHN patients have 
shown antitumor activity of xevinapant. Estimate of LRC at 36 months was 78% (95% CI: 61–88) 
in the xevinapant arm versus 56% (95% CI: 34–73) in the placebo arm, leading to a reduction of 
LRC failure risk of 53% in the xevinapant group compared to the placebo group (Hazard Ratio: 
0.47; 95% CI: 0.19–1·14; P=0.095). 
Xevinapant+CRT treatments also demonstrated a statistically significant and clinically meaningful 
improvement in PFS versus the control group. Estimate of PFS at 36 months was 72% (95% CI: 
56–84) in the xevinapant arm versus 36% (95% CI: 20–51) in the placebo arm, reflecting a 
significant reduction of 66% in the risk of disease progression or death in the xevinapant group 
compared to the placebo group (Hazard Ratio:0.34, [95%CI: 0.17-0.68], P=0.0023). 
Xevinapant combined with CRT also showed a clinically significant improvement in overall survival 
vs the control group. Estimate of overall survival at 36 months was 66% (95% CI: 49–78) in the 
xevinapant arm versus 51% (95% CI: 34–65) in the placebo arm, reflecting a 51% reduction in the 
risk of mortality of any cause in the xevinapant group compared to the placebo group (Hazard 
Ratio:0.49, [95%CI: 0.26-0.92], P=0.0261). 
To date, the observed safety profile associated with xevinapant given alone or in combination 
with chemotherapy, CRT or immunotherapy suggests an acceptable and predictable safety profile 
of the compound. The observed toxicities were in line with those expected in patients with 
advanced solid tumors, and/or with those observed in patients treated with a similar combination 
chemotherapy or CRT regimen. In general, the predominant toxicities were mild 
and/or mostly reversible, could be monitored by routine clinical examinations and were 
manageable by dose delay, dose reduction and/or supportive care. 
Based upon the safety data observed thus far, xevinapant doses of up to 200 mg/day were safely 
combined with either chemotherapy, RT or both. In study -201B, xevinapant was administered to 
patients with LA-SCCHN in combination with cisplatin and standard radiation therapy. An 
increased risk of nausea, mucosal inflammation, dysphagia, weight decrease, radiation skin injury, 
tinnitus, hyperlipasemia, elevation of transaminase and grade 3 anemia were observed versus 
placebo. Nevertheless, the safety profile of xevinapant used in combination with CRT remained 
acceptable and manageable. 
Overall, results from study -201B provide solid preliminary evidence that xevinapant can be safely 
administered in combination with high-dose cisplatin and RT and has the potential to offer 
substantially improved efficacy over the standard of care in high-risk LA-SCCHN. Therefore, the 
benefit/risk is favorable and justifies the clinical investigation proposed to be conducted in the 
study. 
The COVID-19 pandemic affected globally our society in many aspects, including the conduct of 
clinical studies. While patients with cancer are one of the sub-populations at increased risk during 
the pandemic, they are also a patient population in urgent need of receiving treatment for their 
disease. Receiving treatment might make a difference between life and death. Therefore, during 
the COVID-19 pandemic, the decision to start cancer treatment is very individual and relies more 
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than ever on a thorough benefit/risk analysis by the patient in discussion with her/his treating 
physician.  
Recommendations for mitigation Measures during a COVID-19 crisis 
Considerations for participants’ eligibility: 
The safety of the clinical study participants is of primary importance. The individual risk-benefit 
ratio should be carefully evaluated for each of the potentially eligible participants, since 
participants with cancer are at higher risk of severe complications caused by COVID-19 infection. 
Furthermore, special attention should be paid to those participants with additional risk factors for 
more serious COVID-19 infections. 
Recommendations for the initiation of study treatment: 
In the context of the study protocol exclusion criteria #8 “Other infections (viral and/or bacterial 
and/or mycotic) requiring systemic treatment”, a COVID-19 diagnostic test is recommended during 
screening. If the test is performed, the result should be available before randomization. 
Should the test be positive, irrespective of the absence or presence of symptoms, the initiation of 
the study treatment should be postponed. 
If initiation of treatment is postponed, study treatment should not be started before a negative 
COVID-19 test result. Additionally, in case of symptoms study treatment initiation should be 
postponed until resolution of fever without the use of fever-reducing medications and improvement 
in respiratory symptoms (e.g., cough, shortness of breath). 
Once the informed consent has been signed, all the confirmed COVID-19 infections should be 
reported as an AE even if they are asymptomatic. 
 
Recommended study procedures in case of COVID-19 crisis in your area: 
The points mentioned below are intended to provide the Investigator with recommendations for 
the management of the participants enrolled in the study during a COVID-19 crisis. There might 
be specific national legislation and guidance in place, which can be considered to 
complement these recommendations, or, with respect to particular matters, take priority over 
these recommendations.  
 
 
In the case the hospital facility cannot ensure the safety of the study participants during the 
visits despite of all efforts made, the following procedures may be considered: 
 
• 
Certain study assessments, especially those related to safety, such as electrocardiograms 
and blood monitoring (see Section 8.3 of the protocol) can be exceptionally performed in 
institutions other than the study site. More specifically, these assessments can 
exceptionally be performed at local laboratories or relevant clinical facilities 
authorized/certified (as legally required nationally) to perform such tests routinely, if this 
can be done within local restrictions on social distancing. Nevertheless, all procedures 
related to primary endpoint (clinical and radiological evaluations as listed in Section 8.2 of 
the protocol) should be performed at the study site. 
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This decision will be at Investigator’s discretion, based on an assessment of 
potential COVID-19 infection risk between a visit to the study site versus a visit to another 
institution. 
 
Additionally, this exception should also be considered in case of operational limitations at 
the site e.g., overburden of the site laboratories due to management of participants with 
COVID-19.  
 
Assessments done in other institutions will be accepted for study purposes if the data 
generated by those institutions are included in your medical records to allow for study data 
entry and monitoring.  
 
• 
To minimize the likelihood that the participant might run out of Investigational Medical 
Product in case she/he has to skip visits due to the COVID-19 risks, the IMP may be 
shipped from sites to the participant’s residence according to the site internal procedures, 
local laws/regulations for privacy data protection and according to the product 
specifications.  
 
In any case, the sites should inform immediately the CRO and the Sponsor about the 
implementation of such adaptations or measures. 
In case a participant becomes infected with SARS-CoV-2 during the treatment period, consider 
any study treatment modification in the best interest of the participant and in accordance with the 
protocol Section 6.1.2 (Table 6-1). This includes an evaluation of potential drug-drug-
interactions if the use of concomitant medications is necessary to manage the COVID-19 infection 
(see Section 6.5 of the protocol). Any modification to study treatment or use of concomitant 
medication must be clearly documented in the participant’s medical records and reported in the 
study CRF. 
Please note that in case of study treatment discontinuation, it is very important that the participant 
remains in the follow-up of the study to not jeopardize the primary and secondary endpoints data 
collection.  
 
Recommendations for the implementation of Remote Source Data Verification (rSDV): 
In justified exceptional cases and only to the extent strictly necessary, rSDV can take place. In 
case of rSDV implementation at some point, the supplementary recommendations of BfArM and 
PEI to the European Guidance on the Management of Clinical Trials during the COVID-19 
(Coronavirus) pandemic will be followed. 
 
Conclusions: 
These measures are considered adequate to further minimize the risks to participants during the 
COVID-19 pandemic. Thus, the benefit/risk for the study during the COVID-19 pandemic is 
considered to remain favorable. 
Any activity related to implementation of these temporary measures will be captured in the Trial 
Master File for the study and will be described in the Clinical Study Report. 
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13.8. 
Country-Specific Amendment for Japan  
With the following additions and exceptions, all country-specific protocol requirements are outlined 
within the protocol. 
Japan 
5.1 Inclusion Criteria, Item 11, Breastfeeding 
Participants should refrain from breastfeeding during and until at least 3 days (e.g., 5 terminal half-
lives) after the end of the xevinapant/placebo treatment. 
5.1 Clarification to Inclusion Criteria, Item 11, Women of childbearing potential 
Participants suspected to be pregnant by the investigator even if a serum pregnancy test is 
negative will not be eligible. 
5.2 Exclusion Criteria, Item 7, HBV 
HBsAb will be tested for the participants enrolled in Japan. If HBsAb is positive, quantitate HBV-
DNA will be tested. If HBV-DNA is ≥20 IU/ml along with HBsAb being positive, the participant will 
be excluded from the study. 
Note on measures to be taken to ensure the safety of participants: Investigators will continue to 
monitor HBV reactivation during the study treatment based on the Japanese HBV guidelines for 
immuno- and chemotherapy. 
8.1.3 Contraception 
Contraceptive measures which are considered highly effective comprise combined (estrogen and 
progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal*, transdermal*), progestogen-only hormonal contraception associated with inhibition 
of ovulation (oral*, injectable*, implantable*), intrauterine device, intrauterine hormone-releasing 
system, bilateral tubal occlusion, vasectomized partner and sexual abstinence. *Not approved in 
Japan. 
Tolerability assessment 
The safety and tolerability of Japanese participants will be assessed in the initial 9 participants to 
be recruited in Japan using the DLT-like criteria shown below. The safety and tolerability will 
be assessed during the initial 5 weeks for each participant (= DLT-like assessment period).  
The IDMC will review the safety data in an unblinded manner and make a recommendation on the 
acceptability of continuation of recruitment of Japanese participants. 
1. If the incidence of DLT-like adverse events is <40% in the xevinapant arm, treatment will 
be determined to be tolerable. 
2. If the incidence of DLT-like adverse events is ≥40% in the xevinapant arm, tolerability will 
be assessed by the IDMC after referring to the safety in non-Japanese and Japanese 
participants for both the xevinapant and placebo arm, as well as other existing clinical 
information, and also taking the limitation of small sample size into consideration.  The 
IDMC will make a recommendation on the enrollment of additional participants for further 
safety and tolerability assessment, withholding further recruitment in Japan, or continuing 
recruitment. 
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3. If there are ≤2 Japanese participants amongst the first 9 participants randomized 
to the xevinapant/CRT arm, enrollment will be continued up to a total of 12 participants. 
4. If amongst the participants enrolled into the xevinapant/CRT arm, it is still difficult to 
determine tolerability, additional participants from Japan will be enrolled until there are an 
additional three participants in the xevinapant/CRT arm. Assessment of tolerability will 
thereafter be repeated. 
 
DLT-like criteria were defined as any of the following laboratory abnormalities or treatment-related 
AEs occurring during the DLT-like assessment period that are assessed as related to 
investigational treatment: 
1. Asymptomatic CTCAE Grade 4 neutropenia that persists > 7 days 
2. CTCAE Grade ≥ 3 febrile neutropenia 
3. Grade 4 Thrombocytopenia without bleeding lasting ≥ 5 days or Grade ≥ 3 
thrombocytopenia with bleeding or requiring platelet transfusion. 
4. CTCAE Grade ≥ 3 non-hematologic toxicity, including but not limited to (also see 
exceptions below) 
• 
Renal function based on eGFR 
5. CTCAE Grade 4 skin or mucosal reactions 
6. A dose of less than 60% of the planned dose of xevinapant per cycle due to treatment-
related AE occurring during the DLT period 
7. CDDP treatment delay > 2 weeks due to a treatment-related AE occurring during the DLT 
period 
8. CTCAE Grade 2 or higher ototoxicity worsening by 2 grades or more from baseline 
9. Any other life-threatening toxicity 
10. Grade 5 toxicity 
Exceptions, 
I. Grade 3/4 nausea, vomiting, and diarrhea will be considered DLTs if they persist > 3 days 
despite optimal therapy. Grade ≥ 3 alopecia, fatigue and anorexia will not be considered 
DLTs 
II. Common CRT related grade 3 toxicities including laryngeal inflammation, skin reaction, 
dysphagia, oral dysesthesia, mucositis, mucosal infection, skin infection, oropharyngeal 
pain, laryngitis, pharyngitis, decreased appetite, salivary duct inflammation, radiation recall 
reaction, and xerostomia will not be considered DLTs 
III. CTCAE Grade ≥ 3 lab abnormalities that are not clinically significant will not be considered 
DLTs 
IV. Amylase increases originating from the salivary gland will also not be considered DLT 
 
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13.9. Country-Specific Amendment for China  
With the following additions and exceptions, all country-specific protocol requirements are outlined 
within this protocol. 
The intention of the China-specific extension cohort is to allow for the collection and analysis of 
data from approximately 106 China Mainland participants to adequately represent the Chinese 
population. A separate analysis evaluating the Chinese population randomized in the global study 
and in the China-specific extension cohort will be conducted. This analysis will be referred to as 
the “overall Chinese population analysis” throughout this document. 
The extension cohort will be opened for enrollment once the necessary approvals to implement 
the extension cohort have been obtained and the randomization of participants to the global ITT 
population has been completed. 
As an exception to Section 6.3, although anticipated to be distributed to CRO and Sponsor team 
at the Primary Analysis of the global study, the randomization codes for China Mainland 
participants included in the global ITT population will be maintained blinded to the study 
participants and Investigators/site personnel until the overall Chinese population analysis. In 
addition, randomization codes for all participants randomized in the China-specific extension 
cohort will be kept confidential and maintained blinded to the study participants, Investigators/site 
personnel, CRO and Sponsor team until the overall Chinese population analysis. However, 
randomization codes will be disclosed to the third party laboratory in charge of bioanalytical assays 
 to prevent analyses of placebo participants’ samples while allowing 
sample analysis within the sample stability period. 
Overall Chinese population analysis 
Participants from China Mainland enrolled prior to global enrolment completion (n=700) will be 
included in the global ITT population for Primary Analysis. 
A separate analysis referred to as the “overall Chinese population analysis” will be performed. The 
sample size for this analysis will comprise approximately 106 China Mainland participants, as 
follows:  
• 
China Mainland participants randomized into the global study, who will also be included in 
the Primary Analysis based on the global ITT population (approximately 700 participants).  
• 
Additional China Mainland participants randomized into the China-specific extension 
cohort. These participants will not be part of the global ITT population. 
Therefore, the sample size of the overall Chinese population analysis will correspond to 
approximately 15% of the global ITT population, based on a sample size of 700 participants.  
As outlined in Section 10.3, the overall Chinese population will follow the same ITT principle, and 
accordingly the China-specific Safety
 analysis sets will be defined and used 
for the planned analysis of data from the approximately 106 China Mainland participants. 
The statistical considerations described in Section 10.4 are applicable for the overall Chinese 
population analysis with the following exceptions: 
• 
General approach: no inferential test will be performed. The primary and secondary 
efficacy objectives will be summarized in the predefined order specified in Section 10.1 but 
the hierarchical testing procedure is not applicable. The objective of the overall Chinese 
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population analysis is to evaluate the HR from the analysis of EFS as assessed by the 
BIRC, and the analyses for other endpoints are considered as supportive. 
• 
Analysis of the Primary Efficacy Endpoint: the log-rank test is not applicable. 
• 
Analysis of the Secondary Efficacy Endpoints: as specified in the general approach, the 
testing procedure is not applicable. 
• 
Safety analyses: In addition to the analyses in Section 10.4.4, safety analyses for the 
overall Chinese population as well as for the pooled population (global safety analysis set 
combined with the China-specific extension cohort) will be performed at the same cut-off 
date. 
• 
Planned analyses: the overall Chinese population analysis will be triggered once 65 EFS 
events are observed in China Mainland participants, and it is anticipated to occur 1 year 
after the Primary Analysis based on the global ITT population. The consistency of the 
results in EFS between the global ITT population and the overall Chinese population is 
demonstrated if the observed risk reduction for EFS events in the Chinese population is at 
least 50% of the observed risk reduction in Primary Analysis of the global ITT population. 
Assuming the same HR of 0.73 for the benefit in EFS, an overall number of approximately 
106 China Mainland participants with 65 EFS events provides at least 75% probability of 
achieving consistent results in EFS between the global ITT population and the overall 
Chinese population.  
• 
Subgroup analyses: the subgroup analysis by region will not be performed for the overall 
Chinese population analysis. Other subgroup analyses according to Section 10.4.8 will be 
considered as exploratory. 
Further details on the analyses specific to the Chinese extension cohort are provided in the 
statistical analysis plan. 
Prohibited or concomitant use of traditional Chinese medicines 
Any traditional Chinese medication with approval for use as anticancer treatment (regardless of 
the type of cancer) will not be permitted during study treatment. Traditional Chinese medicines for 
indications other than anticancer treatment, such as supportive care, may be administered at the 
discretion of the Investigator. Any traditional Chinese medicines or herbal supplement, if known to 
be strong inhibitors/inducers of CYP 3A4 or inhibitors of P-gp, will not be permitted. Use of 
traditional Chinese medicines as part of next line of anticancer treatment should be documented 
as such. 
 
 
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13.10. Protocol Amendment History  
The information for the current amendment is on the title page.  
 
Section # and Name 
Description of Change 
Brief Rationale 
Version 
Implemented 
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Section # and Name 
Description of Change 
Brief Rationale 
Version 
Implemented 
Appendix 13.3 
Addition of further wording in the 
cisplatin hydration guideline to 
consider a more extensive 
hydration regimen under certain 
circumstances. 
Further mitigation and 
management of renal toxicities 
guidance added to prevent 
nephrotoxicity in high risk 
patients 
10.0 
1.1 Synopsis 
3 Objectives and 
Endpoints 
Time to locoregional control and 
distant metastasis changed from 
assessment by BIRC to 
assessment by Investigator. 
After an initial EFS event has 
occurred, the participant will 
enter the OS follow-up and no 
further imaging for tumor 
assessment will be collected 
according to the protocol. 
Therefore, BIRC will not be able 
to assess distant metastasis in 
case the first event was local 
recurrence or vice versa. In 
contrast, the Investigator will still 
have information on subsequent 
events and can provide them. 
Hence, assessment of these 
endpoints has been changed 
from BIRC to Investigator 
assessment. 
9.0 
1.1 Synopsis 
5 Study Population 
5.5 Strategies for 
Recruitment and 
Retention 
Number of study sites changed 
from approximately 200 to 280. 
Additional sites are opened to 
support study recruitment. 
 
9.0 
1.1 Synopsis 
5.1 Inclusion Criteria 
8.1.2 HPV Status in 
Participants with OPC 
Addition of p16 cutoff definition for 
determination of HPV status for 
OPC participants. 
To ensure consistency and 
alignment between local sites 
and central laboratory on HPV 
status determination for OPC 
participants. 
9.0 
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Section # and Name 
Description of Change 
Brief Rationale 
Version 
Implemented 
1.1 Synopsis 
1.3 Schedule of 
Assessments  
3 Objectives and 
Endpoints 
6.1.2.1 Xevinapant or 
Matched Placebo 
8.3.8 Participant Diary 
 
 
 
 
 
 
 
 
 
 
1.1 Synopsis 
4.1 Study Design and 
Overview 
10 Statistical 
Considerations 
Figure 3, Figure 4-1 and 
Table 10 updated to reflect the 
change from follow-up analysis to 
final analysis  
A final analysis was added 
which is OS event driven and 
replaces the follow-up analysis. 
9.0 
1.1 Synopsis 
5.2 Exclusion Criteria 
 
#18 - History of other 
malignancies:  
T1a squamous esophageal 
carcinomas added as an 
exception.  
SCCHN patients with early 
squamous cell carcinoma of the 
esophagus (ESCN) are similar 
in prognosis as patients without 
ESCN and therefore can be 
considered eligible for clinical 
studies as the natural history 
and treatment does not have the 
potential to interfere with the 
safety or efficacy assessment of 
the investigational drug. 
9.0 
 
#19: Contraindication changed to 
include both MRI and CT scans 
Participants able to undergo 
either enhanced MRI or 
enhanced CT can enter the 
study. 
 
1.1 Synopsis 
5 Study Population 
5.5 Strategies for 
Recruitment and 
Retention 
10.2.1 Sample Size 
Assumed screening failure rate 
changed to 30% with 
approximately 1000 participants 
being screened. 
Based on the currently observed 
screening failure rate the 
numbers have been adjusted. 
9.0 
1.3 Schedule of 
Assessments 
Section 8.3.6 
Electrocardiograms 
Remove ECG assessment at C4.  
Available data do not suggest 
xevinapant has long-term effects 
on ECG.   
9.0 
1.3 Schedule of 
Assessments 
8.3.7 Laboratory Tests 
13.2 Cisplatin 
Administration 
Additional renal function 
monitoring to take place 48 hours 
(±12 hours) after cisplatin 
infusion. 
Monitoring included to avoid or 
mitigate renal toxicities. 
9.0 
4.1 Study Design and 
Overview 
6.3 Measures to 
Minimize Bias 
 
Introduction of a Firewall Team as 
an additional oversight 
committee. 
Added to keep the study team 
blinded at Interim Analysis until 
a decision is made if the results 
are sufficient for a regulatory 
filing.  
9.0 
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Section # and Name 
Description of Change 
Brief Rationale 
Version 
Implemented 
11.2.1 Independent 
Data Monitoring 
Committee 
6.1.2.3.1 Treatment 
Interruption 
Compensation of missed RT 
fractions can be administrated at 
the end of treatment or during 
treatment at least 6 hours apart. 
To facilitate treatment delivery 
as per local policies and reduce 
participant and site burden. 
9.0 
6.5.2 Medications to be 
Used with Caution 
6.5.3.1.3 CYP3A4 low 
therapeutic index drugs 
or sensitive substrates 
Midazolam and alfentanil added 
to Table 6-8. 
Alfentanil removed from Table 6-
5. 
Apixaban removed from Table 6-6  
(kept in Table 6-8) 
Since xevinapant has the 
potential to strongly inhibit 
CYP3A4/5, the CYP3A4 
sensitive substrates midazolam, 
apixaban, alfentanil, which may 
be used for the study population, 
are now added to the prohibited 
medication list (Table 6-8). 
9.0 
6.5.3.3 Prohibited or 
concomitant use of 
traditional Chinese 
medicines 
New section on prohibited or 
concomitant use of traditional 
Chinese medicines added 
Traditional Chinese medicine is 
employed to treat or prevent 
health problems. Use of 
traditional Chinese medicine 
may have an effect on efficacy 
and outcome of the study 
objectives.   
9.0 
6.5.3.5 6 Use of Other 
Investigational Agents 
and Devices 
6.5.3.6 Use of 
Anticancer Treatments 
Prohibition of treatment with an 
investigational agent other than 
xevinapant/placebo, use of other 
anticancer treatment or use of an 
investigational device added 
To avoid overlapping efficacy or 
toxicity effects in the study 
disease that would impact the 
safety of the patient or the 
outcome of the study 
9.0 
Section 7.2 End of 
study 
Definition of EOS updated to 
include the event-driven final OS 
analysis. 
The event driven final OS 
analysis is added that specifies 
the OS testing strategy 
regarding effect size, control of 
the type I error, power, and 
number of events. 
9.0 
7.3 Premature Study 
Withdrawal  
Addition of details on the reasons 
for withdrawal of participants from 
study by Investigator. 
Provide clarity for Investigator of 
when a participant may be 
withdrawn from the study at his 
discretion.  
9.0 
7.3 Premature Study 
Withdrawal  
9.4.2 Pregnancy 
Removal of pregnancy as a 
trigger for premature withdrawal 
from study. 
Note: Pregnancy will remain a 
reason for discontinuation from 
study treatment. 
 
There are no procedures during 
the OS follow up period that 
could interfere with pregnancy. 
Therefore, pregnancy is not a 
reason to be discontinued from 
the study, and these participants 
should be followed up for OS.  
9.0 
8.2.2 Clinical 
Assessment 
Decision tree for the 
determination of tumor status 
added (Figure 8-1). 
To help investigators with 
clinical assessment when 
histopathology results or other 
clinical data are not consistent 
with the radiology report. 
9.0 
10.1.2 Secondary 
Efficacy Hypothesis  
Update of the secondary 
endpoints to be used for the 
hierarchical testing procedure. 
To focus on OS only, as OS is 
the most reliable endpoint 
regarding clinical benefit and 
9.0 
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Section # and Name 
Description of Change 
Brief Rationale 
Version 
Implemented 
complements the primary 
endpoint EFS. . 
10.2.1 Sample Size 
Determination  
10.2.2 Robustness of 
Sample Size 
10.4.7 Planned Analysis 
Non-binding futility analysis for 
the primary endpoint EFS added. 
To provide guidance for the 
IDMC via a futility boundary for 
the primary endpoint EFS at the 
interim analysis. 
9.0 
 
Testing strategy for the secondary 
endpoint OS was specified. 
To specify the OS testing 
strategy regarding effect size, 
control of the type I error, power, 
number of events. 
 
10.4. Statistical 
Analyses 
Cox Model: Method how to 
handle ties was updated.  
In case of a high number of ties, 
which is the case in the situation 
of predefined scan intervals, a 
more appropriate method how to 
handle ties is replacing the 
proportional hazards model by 
the discrete logistic model. 
9.0 
10.4.4.1 Adverse 
Events 
Definition of TEAE. 
Time period was specified for 
clarity. 
9.0 
13.5 Response 
Evaluation Criteria in 
Solid Tumors (RECIST) 
V1.1 applied to this 
study in locally 
advanced SCCHN 
RECIST v1.1 revised by adding 
guidance on assessment for LA 
SCCHN.  
Revised for clarity. 
9.0 
13.9 Country-specific 
Amendment for China 
Country-specific Amendment for 
China added (v8.1 CHN) 
To allow for the collection and 
analysis of data from 
approximately 106 China 
Mainland participants to 
adequately represent the 
Chinese population. 
9.0 
Throughout document 
Minor editorial and document 
formatting changes. 
Minor, therefore changes have 
not been summarized. 
9.0 
Synopsis: Study 
Population and Sample 
Size 
Section 4.1: Study 
Design and Overview 
Section 5: Study 
Population 
Section 5.5: Strategies 
for Recruitment and 
Retention. 
Section 10.2.1: Sample 
Size 
Added wording on the addition of 
a China-specific extension cohort. 
An additional China-specific 
extension cohort is added to 
increase the sample size of the 
overall Chinese population to 
approximately 15% 
(106 subjects) of the global ITT 
population, to adequately 
represent the Chinese 
population. 
8.1 
Section 10.3: Analysis 
Populations 
Added wording on global study 
population. 
Clarify that the analyses sets in 
this section are described for the 
global study population.  
8.1 
Section 11.3.2: Future 
Use of Stored 
Specimens and Data 
Explanation added that for China, 
the use of remaining samples will 
Clarify the future use of 
specimen in China. 
8.1 
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Section # and Name 
Description of Change 
Brief Rationale 
Version 
Implemented 
be in accordance with local 
regulation. 
Section 13.9: Country-
specific Amendment for 
China 
New 
country-specific 
section 
added to include information on 
the inclusion of a China-specific 
extension cohort. The analysis of 
the overall Chinese population is 
described. 
An additional China-specific 
extension cohort is added to 
increase the sample size of the 
overall Chinese population to 
approximately 15% 
(106 subjects) of the global ITT 
population, in order to 
adequately represent the 
Chinese population.  
8.1 
Wording 
added 
to 
prohibit 
traditional Chinese medicine for 
anticancer treatment and if they 
are 
known 
to 
be 
strong 
inhibitors/inducers of CYP 3A4 or 
inhibitors of P-gp. 
Traditional Chinese medicine is 
employed to treat or prevent 
health problems. Use of 
traditional Chinese medicine 
may have an effect on efficacy 
and outcome of the study 
objectives.   
8.1 
Section 13.10: Protocol 
Amendment History 
Addition of the last amendment 
(V8.0).  
Changes made in V8.0 have 
now become part of the 
amendment history. 
8.1 
Throughout Document 
Minor editorial and document 
formatting changes. 
Minor, therefore changes have 
not been summarized. 
8.1 
Entire document 
Merck KGaA, Darmstadt, 
Germany replaces Debiopharm 
Changed “Debio 1143” to 
“xevinapant” as applicable 
Updated due to change in 
sponsors 
8.0 
Updates to Title Page 
section 
Added protocol amendment 
history 
Added Merck KGaA, Darmstadt, 
Germany protocol number 
MS202359 _0006 
To align with sponsor standards 
8.0 
Section 1.1 
MS202359 _0006 
Added new study number 
8.0 
Table 1-1, Footnote 12 
For subjects switching to 
carboplatin on C2D2 
and/orC2D3 C3D2, 1 additional 
 sample should 
be collected at the end of the 
carboplatin infusion. 
To align with Section 8.4.1 
8.0 
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Section # and Name 
Description of Change 
Brief Rationale 
Version 
Implemented 
Section 4.3 
Tumor penetration and target 
engagement (IAP1 degradation) 
in the tumor was shown in 
Phase 2 studies Debio 1143-201 
and Debio 1143-SCCHN-202. In 
the blood, Ttarget engagement 
In the study Debio 1143-
HCCHN-202, intratumoral 
pharmacokinetic (PK) 
measurements identified high 
Debio 1143 tumor penetration 
and distribution, largely 
exceeding the IC50 of IAPs, 
which are the targets of Debio 
1143, by 100 to 1000-fold at the 
dose level of 200 mg. 
Clarified PK outcomes 
8.0 
Section 6.1.2.1.2, Table 
6-1 
In Hearing Impaired row, 1st 
occurrence: 
For subjects on carboplatin or 
switching to carboplatin: 
resume treatment at AUC=4. 
Subjects do not switch to 
carboplatin from carboplatin 
8.0 
Section 6.1.2.3. 
An elective intermediate 63 Gy 
volume at the periphery of the 
PTV (1.8 Gy/fraction per week 
[5/7 days]) is not recommended 
but if it is used will not be 
considered as a deviation 
(Hodapp 2012; Garden et al. 
2013; Daly et al. 2010). 
Deleted to align with Intensity 
Modulated Radiation Therapy 
manual and international 
guidelines 
8.0 
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Section # and Name 
Description of Change 
Brief Rationale 
Version 
Implemented 
Sections 9.3 and 9.4.2 
Updated SAE reporting 
information: 
If for any reason the eCRF is not 
available, as a backup option, the 
SAE can be declared by email at 
SafetyReporting@SyneosHealt
h.com Safety-Debio-1143-
301@debiopharm.com using the 
Debiopharm International (DPI) 
paper “SAE report form” 
1-877-464-7787 41 21 321 06 97 
Updated due to change in 
sponsors 
8.0 
Section 13.8 
Country-specific Amendment 
for Japan added 
To incorporate changes 
requested by the local health 
authority 
8.0 
Section 13.10 
Moved and updated Protocol 
Amendment History (formerly 
Section 11.4.1.2.1.1.1.1 and 
currently Section 11.5) to 
Section 13.9 
To align with sponsor standards 
8.0 
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Section # and Name 
Description of Change 
Brief Rationale 
Version 
Implemented 
Section 13.11 
Updated and moved Sponsor 
Signature Page 
To align with sponsor standards 
8.0 
Section 13.12 
Updated and moved 
Coordinating Investigator Page 
To align with sponsor standards 
8.0 
Section 13.13 
Updated and moved Principal 
Investigator Page 
To align with sponsor standards 
8.0 
Section 6.1.2.1.2, Table 
6-1 
In Hearing Impaired row, 1st 
occurrence: 
For subjects on carboplatin or 
switching to carboplatin: resume 
treatment at AUC=4. 
Subjects do not switch to 
carboplatin from carboplatin 
7.2 
Section 13.8 
5.1 Clarification for Inclusion 
Criteria, Item 11, Women of 
childbearing potential 
Participants suspected to be 
pregnant by the investigator 
will not be eligible even if a 
serum pregnancy test is 
negative. 
Per health authority 
requirements 
7.2 
Section 13.8 
Note on measures to be taken to 
ensure 
the 
safety 
of 
participants: Investigators will 
continue 
to 
monitor 
HBV 
reactivation during the study 
treatment 
based 
on 
the 
Japanese HBV guidelines for 
immuno- and chemotherapy. 
Per health authority 
requirements 
7.2 
Section 13.8 
4. CTCAE Grade 
≥ 3 
non-
hematologic toxicity, including 
but not limited to (also see 
exceptions below) 
• 
CTCAE Grade 3 or higher 
worsening of renal Renal 
function based on GFR 
Per health authority 
requirements 
7.2 
Section 13.8 
6. CDDP and/or xevinapant A 
dose of less than 60% of the 
planned dose of xevinapant 
per cycle due to treatment-
related AE occurring during 
the DLT period 
Per health authority 
requirements 
7.2 
Section 13.8 
7. CDDP 
and/or 
xevinapant 
treatment delay > 2 weeks due 
to 
a 
treatment-related 
AE 
occurring 
during 
the 
DLT 
period 
Per health authority 
requirements 
7.2 
Entire document 
Merck KGaA, Darmstadt, 
Germany replaces Debiopharm 
Updated due to change in 
sponsors 
7.1 
Updates to Title Page 
section 
Added protocol amendment 
history 
To align with sponsor standards 
7.1 
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Section # and Name 
Description of Change 
Brief Rationale 
Version 
Implemented 
Table 1-1, Footnote 12 
For subjects switching to 
carboplatin on C2D2 and/orC2D3 
C3D2, 1 additional 
 
sample should be collected at the 
end of the carboplatin infusion. 
To align with Section 8.4.1 
7.1 
Section 4.3 
Tumor penetration and target 
engagement (IAP1 degradation) 
in the tumor was shown in 
Phase 2 studies Debio 1143-201 
and Debio 1143-202. In the 
blood, Ttarget engagement 
In the study Debio 1143-HCCHN-
202, intratumoral pharmacokinetic 
(PK) measurements identified 
high Debio 1143 tumor 
penetration and distribution, 
largely exceeding the IC50 of 
IAPs, which are the targets of 
Debio 1143, by 100 to 1000-fold 
at the dose level of 200 mg. 
Clarified PK outcomes 
7.1 
Section 6.1.2.3. 
An elective intermediate 63 Gy 
volume at the periphery of the 
PTV (1.8 Gy/fraction per week 
[5/7 days]) is not recommended 
but if it is used will not be 
considered as a deviation 
(Hodapp 2012; Garden et al. 
2013; Daly et al. 2010). 
Deleted to align with Intensity 
Modulated Radiation Therapy 
manual 
7.1 
Sections 9.3 and 9.4.2 
Updated SAE reporting 
information: 
If for any reason the eCRF is not 
available, as a backup option, the 
SAE can be declared by email at 
SafetyReporting@SyneosHealt
h.com Safety-Debio-1143-
301@debiopharm.com using the 
Debiopharm International (DPI) 
paper “SAE report form” 
1-877-464-7787 41 21 321 06 97 
Updated due to change in 
sponsors 
7.1 
Section 13.8 
Country-specific Amendment for 
Japan added 
To incorporate changes 
requested by the local health 
authority 
7.1 
Section 13.9 
Moved and updated Protocol 
Amendment History (formerly 
Section 11.4.1.2.1.1.1.1) to 
Section 13.9 
To align with sponsor standards 
7.1 
Section 13.10 
Updated and moved Sponsor 
Signature Page 
To align with sponsor standards 
7.1 
Section 13.11 
Updated and moved Coordinating 
Investigator Page 
To align with sponsor standards 
7.1 
Section 13.12 
Updated and moved Principal 
Investigator Page 
To align with sponsor standards 
7.1 
 
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13.10.1. 
Protocol Amendments 1 through 6  
The amendment must be approved by the Sponsor and, if substantial as defined in directive 
2001/20/EC or other local applicable regulations, submitted for approval to the Health Authorities 
and IEC/IRB prior to being implemented. If the change implies a modification of treatment or of 
subject evaluation tests, a new version of the ICF must be prepared and submitted for approval 
to Health Authorities and the IEC/IRB. The Sponsor will assume any responsibility or liability 
resulting from a change in the protocol, only if the change has been approved in writing by himself, 
the Health Authorities, and the IEC/IRB. 
 
13.10.1.1. 
Protocol Amendment History Prior to Merck KGaA Sponsorship  
13.10.1.1.1. 
Amendment 1 - 12 May 2020  
The original protocol (V1.0 dated 02 April 2020) was amended on 12 May 2020 (V2.0 dated 12 
May 2020) to correct a typo in the gender specific QTcF values mentioned in the exclusion criterion 
16. The standard QTcF values for male and female patients were unintentionally reversed in the 
original protocol. 
13.10.1.1.2. 
Amendment 2 - 2 July 2020  
The protocol V2.0 dated 12 May 2020 was amended on 2 July 2020 (V3.0 dated 2 July 2020) 
further to modification requests from Regulatory Authorities. These requests included: 
• 
The addition of a recommendation on cryoconservation of sperm prior to treatment 
because of the possibility of infertility due to therapy with cisplatin, carboplatin or Debio 
1143. 
• 
The addition of an ECG examination before starting Cycle 4 with Debio 1143 monotherapy. 
• 
The addition in the prohibited medication list of live-attenuated vaccinations during the 
treatment with Debio 1143/matched placebo and up to 90 days after the end of treatment. 
• 
 
 
• 
A clarification of the assumptions used for the sample size calculation. 
• 
A clarification of dynamic allocation. 
In addition, the following changes were made: 
• 
Correction regarding laboratory assessments: all laboratory parameters included in the 
full hematology and full chemistry panels will be performed centrally even if they are 
performed locally. Estimated volume of blood collected during the study remains 
identical. 
• 
Throughout the protocol, minor edits, clarifications, correction of typographical errors 
and formatting were made to improve readability. 
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13.10.1.1.3. 
Amendment 3 - 23 July 2020  
Protocol V3.0 dated 2 July 2020 was amended on 23 July 2020 (V4.0 dated 23 July 2020) to 
clarify the randomization procedure as requested by Regulatory Authorities. 
13.10.1.1.4. 
Amendment 4 - 6 December 2020  
Protocol V4.0 dated 23 July 2020 was amended on 6 December 2020 (V5.0 dated 6 December 
2020) further to modification requests from the French Regulatory Authority Agence Nationale de 
Sécurité du Medicament et des produits de Santé (ANSM). 
To answer those requests the following modifications were made to the protocol: 
• 
Exclusion of patients with hypersensitivity to the active substances or other compounds 
containing platinum. 
• 
Additional information on the management and dose modification of the Investigational 
Medicinal Products in case of hemolytic uremic syndrome. 
• 
Additional information on the management and dose modification of the Investigational 
Medicinal Products in case of allergic reactions. 
• 
Addition of an optional audiogram before each new cycle of cisplatin throughout the study, 
as required per the cisplatin prescribing information. 
• 
Additional information on the prohibited medications and medications to be used with 
caution in combination with cisplatin and carboplatin, following the prescribing information 
of these products. 
• 
Clarifications on the timing of study procedure: 
o The wording of the inclusion criteria number 8 was modified to clarify that an 
audiogram must be performed at screening, in alignment with the initial instructions 
provided in the Section 8.3.5 Audiogram. 
o The Section 8.1.1 Baseline Disease Characteristics and Assessments was 
updated accordingly. 
• 
Other modifications: 
o The new International Nonproprietary Name of Debio 1143 (xevinapant) was 
introduced in the protocol. 
o Throughout the protocol, a few minor edits were made. 
 
13.10.1.1.5. 
Amendment 5 - 7 December 2020  
Protocol V5.0 dated 6 December 2020 was amended on 7 December 2020 (V6.0 dated 7 
December 2020) to include the following modifications: 
Clarifications on the primary endpoint: 
• 
The time window for primary treatment failure, which is one of the EFS components, was 
clarified as follows: only events occurring during the treatment period, and up to the EOT visit, 
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are considered as primary treatment failures. This rule aims to correct for potential bias in the 
follow-up schedules for tumor assessment. 
 
Clarifications on statistical analyses: 
• 
The stratification factors to be used for the statistical test of the EFS, PFS, OS and all time-to-
event analyses were clarified. The list of stratification factors is now limited to tumor size and 
lymph node involvement, but the type of test remains the same (stratified log-rank test). The 
4 randomization factors originally proposed would result in 36 strata, which could lead to 
sparse sample size in some strata. The stratification factors retained are considered the most 
relevant while assuring sufficient sample size. 
• 
Correction of a typo in the Table 10 4 Robustness of sample size for OS: the title of the column 
mentioning Expected Number of Death Events and Expected Power provided should read 
Primary Analysis instead of Follow up analysis. 
 
Extension of safety data collection: 
• 
The time window for collection of SAEs and late onset AESIs unrelated to study treatments 
was extended during the follow-up period as follows: 
o SAEs will be collected until the EOS visit regardless of their relationship with study 
treatments. Previously only SAEs considered related to study treatments were to be 
collected during the follow-up period. 
o Late onset AESIs will be collected from the EOT until the EOS visit regardless of their 
relationship with study treatments. Previously, only late onset AESIs related to study 
treatments were to be collected from Month 7 until the EOS visit. 
• 
Clarifications on the reporting of death when related to disease progression: only death 
attributed by the Investigator as solely due to disease progression are not considered as 
SAEs. 
• 
Clarification that AE, SAE and AESI data will be collected for all study treatments, including 
IMRT. 
 
Clarifications on data collection: 
• 
The EFS data collection starting date was added in the Study Diagram. 
• 
The row “EFS data collection” was added to the Tables of assessment 1-1 as a reminder to 
collect EFS data status throughout the study. 
• 
The row “Progression status (until potential EFS event)” was renamed “EFS data collection” 
for clarity. The parentheses around the arrow which indicated that the EFS data collection 
follow-up was to be performed until an EFS event was removed for consistency with the lack 
of parenthesis for the row “Survival status”. 
• 
Pregnancy was added as a reason for premature study withdrawal in Section 7.3, for 
consistency with the safety Section 9.4.2. 
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• 
The study flow chart was modified to clarify that the EOT will occur 15 days after last study 
treatment administration (Debio 1143, placebo, chemotherapy or IMRT) not only Debio 
1143/placebo treatment, in alignment with the Study assessment table. 
• 
Removal of an instruction regarding data collection in case of rescreening to avoid redundancy 
within the same section and given that all data are collected in the same database (Section 
5.4 Screen failure). 
 
Modifications on the timing of study procedures: 
• 
The timing of approval of the IMRT plan by RT-QA Review Center was modified as follows: 
the IMRT plan should be approved before the start of radiotherapy instead of before 
randomization. This change does not impact the eligibility of a patient for the study. In addition, 
a mention to the approval of the IMRT plan by the RT-QA Review Center prior to the start of 
the IMRT was added in the Section 1.3 Schedule of Assessment for consistency. 
• 
Alignment with the ITT analysis principles: if several i.v. contrast-enhanced CT scans/MRI of 
the head and neck and CT scans of the chest are available before treatment start, the closest 
imaging to randomization, instead of Cycle 1 Day 1, will be used as baseline. 
• 
Physical examination abnormalities are to be recorded as an AE if started on or after ICF 
signature instead after randomization. 
 
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Clarifications regarding chemotherapy administration: 
• 
A cross reference to Section 6.1.2.1.2 was added in the synopsis and included the dose of 
carboplatin to be used in case of toxicity after the first cisplatin dosing. 
• 
A reminder to consult and follow cisplatin administration instructions provided in the local label 
was repeated in Section 6.1.2.2. 
• 
The description of the reconstitution of cisplatin in Section 13.2 was removed given that the 
cisplatin formulation provided to sites does not need to be reconstituted. 
 
Other modifications: 
• 
Additional information on the RT-QA Review Centers selected for the study was added. 
13.10.1.1.6. 
Amendment 6 – 28 June 2021  
The protocol for study Debio 1143-SCCHN-301 version 7.0 dated 28 June 2021 has been 
amended to reflect the following changes: 
 
Modification of inclusion criterion number 8 
Most adults with clinically normal hearing demonstrate some evidence of mild hearing loss at 
certain frequencies by pure tone audiometry test. The current inclusion criterion number 8 stating 
“No hearing loss by clinical assessment and audiogram”, appears to exclude these patients, even 
though clinically the Investigators would proceed with cisplatin-radiation therapy as the gold 
standard curative-intent treatment. The inclusion criterion number 8 has been modified as follows: 
No hearing loss by clinical assessment or ≤ grade 2 hearing impairment (according to NCI-CTCAE 
v.5). 
 
Granulocyte-Colony Stimulating Factors (G-CSF) use 
The study IDMC requested to exclude prophylactic use of G-CSF and provide further guidance on 
its use in the protocol. The following explanation has been included in Section 6.5.4: 
Granulocyte-Colony Stimulating Factors (G-CSF) are not allowed throughout the screening period 
and for prophylaxis. Nevertheless, for subjects presenting with febrile neutropenia who have risk 
factors for infection-related complications or poor clinical outcome, therapeutic G-CSF including 
secondary prophylaxis should be considered (Becker et al. 2020). Features associated with poor 
outcome include age >65 years, sepsis syndrome, ANC <100 neutrophils/m3, anticipated 
prolonged (>10 days) neutropenia, pneumonia or other clinically documented infection, invasive 
fungal infections, and hospitalization at the time of fever. 
In Table 6-1 (neutrophil count decrease row), the note stating that “the use of granulocyte colony-
stimulating factor (G-CSF) prophylaxis is recommended if chemotherapy is continued” has been 
removed to be consistent with the IDMC request. 
 
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Abnormal QTcF prolongation definition and triplicate ECG recordings 
An inconsistency in the current protocol version 6.0 concerning the definition of abnormal QTcF 
prolongation requiring a triplicate ECG recording has been detected between Section 9.1.3 and 
Section 8.3.6. 
In Section 9.1.3, abnormal QTcF prolongation is defined when at least 2 consecutive ECG 
readings show an increase of more than 30 ms compared to the baseline value. 
In Section 8.3.6, a triplicate ECGs is requested when a significant prolongation of >500 ms or 
change from baseline of >60 ms is observed. 
The definition of abnormal QTcF prolongation requiring a triplicate ECG recording has been 
modified in Section 8.3.6 as follows: “In case of abnormal ECG findings (e.g., QTcF prolongation 
>30 ms compared to baseline, or QTcF interval >500 milliseconds), ……, triplicate ECG readings 
will be performed”. 
 
Audiometry assessment 
Audiometry is mandatory only at screening. Considering the current COVID-19 pandemic, the 
safety of the study participants is of primary importance since patients with cancer are at higher 
risk of severe complications caused by COVID-19 infection. Therefore, special attention should 
be paid in reducing the unnecessary patients’ visits to the investigational sites, mainly due to the 
execution of complimentary clinical assessments. 
The current protocol version 6.0 includes several sequential audiometry tests. Since audiometry 
at screening is mandatory to evaluate the eligibility of the subject, further audiometry tests may be 
performed only if clinically indicated as per institutional or national guidelines. 
In Section 8.3.5 and in Table 1-1 (footnote 10), the text has been modified as follows: “An 
audiometry must be performed at screening. In addition, hearing clinical evaluation and 
audiometry should be performed at C2D1 and C3D1 if clinically indicated (except for France, see 
Appendix 13.6 and at any time if clinically indicated as per institutional or national guidelines. 
During the follow-up period, an audiometry is to be performed only if clinically indicated, as per 
institutional or national guidelines.” 
The Appendix 13.6 Audiometry assessments has been added to provide the following information 
to investigational sites in France: “As requested by the French ANSM, an audiometry must be 
performed at screening, C2D1 and C3D1 within 5 days before platinum-based chemotherapy and 
at any time if clinically indicated as per institutional or national guidelines. During the follow-up 
period, an audiometry is to be performed only if clinically indicated, as per institutional or national 
guidelines”. 
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Frequency of follow-up contacts for survival status 
To mitigate the potential risk of subjects lost to follow-up during the survival follow-up period, the 
frequency of survival follow-up contacts has been reduced from 6 to 3 months. 
 
Discontinuation of IMRT and subject admission to monotherapy period 
In line with the rationale to include xevinapant monotherapy to increase the subject outcome 
benefit and considering that an ITT analysis will be performed, the inclusion of all the enrolled 
subjects in the monotherapy period is now allowed, even if they received a total radiotherapy dose 
less than 50 Gy. 
In Section 6.1.2.3.1, the text has been accordingly modified as follows: “If IMRT is permanently 
discontinued due to severe and intolerable toxicities as per Investigator’s judgment, then 
Debio 1143/matched placebo monotherapy administration should be maintained.” 
 
Collection of efficacy assessments and Patient-Reported Outcomes (PROs) 
In Section 8.2 the following instructions were added: Tumor assessment and HRQL questionnaires 
or assessments should be continued until disease progression (as per RECIST v1.1) occurs or 
Month 60 post-randomization, whichever occurs first. 
The resulting data will be used in a sensitivity analysis of the secondary efficacy endpoints. 
Even in case of premature discontinuation of treatment in subjects without disease progression 
according to RECIST v1.1 (e.g., unacceptable toxicity), efficacy assessments will continue to be 
performed until disease progression (as per RECIST v1.1) to correctly evaluate all the secondary 
efficacy endpoints or Month 60 post-randomization, whichever occurs first. 
 
Radiological tumor assessments at screening 
Section 1.3, Table 1-1(footnote 4) and Section 5.4 have been modified to clarify that 18F-FDG-PET, 
i.v. contrast-enhanced CT-scan or MRI of head and neck, and CT-scan of chest are only accepted 
if they are performed within 4 weeks before randomization. This will minimize the risk of 
distant metastasis or tumor growth before randomization and the beginning of treatment. 
 
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Xe vi n a p a nt  
Tril y n X  
M S 2 0 2 3 5 9 _ 0 0 0 6  
 
 
 
1 8 3 /1 8 9  
 
 
P h ar m a c o ki n eti c s ( P K) s u b gr o u p e x p a n si o n a n d e xtr a P K s a m pli n g  
To e n s ur e s uffi ci e nt c oll e cti o n of P K d at a t o c h ar a ct eri z e P K di s p o siti o n, t h e ti m e p oi nt s a n d t h e 
e x pl or at or y e n d p oi nt s of t h e D e bi o 1 1 4 3/ pl a c e b o P K bl o o d s a m pli n g h a v e b e e n m o difi e d. T h e n e w 
ti m e p oi nt s ar e C 3 D 8, C 3 D 1 5 a n d C 4 D 1. P K bl o o d s a m pl e s will b e dr a w n pr e d o s e o n C 1 D 1, C 1 D 2, 
C 1 D 8, C 2 D 2, C 3 D 1, C 3 D 2. O n C 3 D 8, C 3 D 1 5, C 4 D 1, t h e P K bl o o d s a m pl e will b e dr a w n at t h e 
ti m e of h e m at ol o g y/ bi o c h e mi str y bl o o d s a m pli n g. A n o pti o n al p h ar m a c o g e n eti c bl o o d s a m pl e will 
b e dr a w n pr e d o s e o n C 1 D 1 ( e x c e pt f or C hi n a).  
T h e P K s a m pl e si z e h a s b e e n e x p a n d e d t o i n cl u d e all t h e e nr oll e d s u bj e ct s.  
T hi s w a s m o difi e d a cr o s s t h e pr ot o c ol i n all t h e r el e v a nt s e cti o n s.  
 
 
 
 
 
R e c o m m e n d ati o n f or t h e S A R S -C o V -2 v a c ci n ati o n d uri n g st u d y tr e at m e nt  
C o n si d eri n g t h e p a n d e mi c sit u ati o n, r e c o m m e n d ati o n s f or t h e S A R S -C o V -2 v a c ci n ati o n d uri n g 
st u d y tr e at m e nt w er e i n cl u d e d i n S e cti o n 6. 5. 1. 2.  
 
C o n d u ci n g t h e st u d y d uri n g t h e C O VI D -1 9 p a n d e mi c  
G er m a n Bf Ar M r e q u e st e d t o p erf or m a b e n efit/ri s k a s s e s s m e nt of t h e c o n d u ct of t h e st u d y d uri n g 
t h e C O VI D-1 9 p a n d e mi c. T hi s h a s b e e n i n cl u d e d i n A p p e n di x 1 3. 7 a n d i s s p e cifi c f or t h e 
i n v e sti g ati o n al sit e s i n G er m a n y. 
 
 
Ci s pl ati n h y dr ati o n g ui d eli n e s  
T E V A ci s pl ati n 1 m g/ ml or ot h er r e gi st er e d ci s pl ati n br a n d s ar e pr o vi d e d f or t h e s t u d y. 
R e c o m m e n d e d h y dr ati o n g ui d eli n e s ( p er T E V A S m P C  v 6. 0 ) ar e pr o vi d e d i n S e cti o n 1 3. 3.  
 
Ar c hi v al t u m or s a m pl e a n d p h ar m a c o g e n eti c s bl o o d s a m pl e f or e x pl or at or y a n al y si s  
A s t h e e x pl or at or y bi o m ar k er s will b e a n al y z e d c e ntr all y o ut si d e C hi n a a n d t h e C hi n e s e 
r e g ul ati o n s d o n ot all o w t h e e x p ort ati o n of s a m pl e s o ut si d e t h e c o u ntr y, t h e c oll e cti o n of b ot h 
ar c hi v al t u m or s a m pl e s a n d p h ar m a c o g e n eti c bl o o d s a m pl e s f or e x pl or at or y a n al y si s ar e n ot 
a p pli c a bl e i n C hi n a.  
T hi s w a s m o difi e d a cr o s s t h e pr ot o c ol i n all t h e r el e v a nt s e cti o n s. 
 
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ECG collection plan at C4D1 
A postdose will be collected at C4D1 prior to the pharmacokinetic sampling and the blood sampling 
to enable calculation of AESI (change from baseline of > 30 ms) at both timepoints (pre-dose and 
post-dose). 
Clarifications: 
• 
Carboplatin administration should follow the local label instructions. 
In Section 6.1.2.2, the text has been modified as follows: “The subject can switch to carboplatin 
in C2 and/or C3 as per the dose modifications outlined in Table 6-1. Please consult and follow 
carboplatin administration instructions provided in your local label.” 
 
• 
Use of albumin transfusions. 
Albumin transfusions are not allowed within 2 weeks before randomization. The text of 
exclusion criterion number 12 has been modified as follows: “Documented weight loss of >10% 
during the last 4 weeks prior to randomization (unless adequate measures are undertaken for 
nutritional support), OR plasmatic albumin < 3.0 g/dL. No albumin transfusions are allowed 
within 2 weeks before randomization.” 
 
• 
Exclusion of subjects suffering from autoimmune diseases requiring treatment with anti 
treatment with antitumor necrosis factors (TNF) medication. 
Subjects suffering from autoimmune disease requiring TNF medication are ineligible. The 
exclusion criterion number 14 has been modified as follows: “Active uncontrolled inflammatory 
disease (including rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, 
severe extensive psoriasis, and other autoimmune diseases) requiring ongoing treatment with 
anti-TNF medication.” 
 
• 
Rules for subject’s rescreening 
It has been clarified that the subject’s rescreening is allowed in case a reversible cause of 
screening failure is adequately treated and/or resolved. The text in Section 5.4 has been 
modified as follows: “Reversible causes of screening failure that were adequately treated 
and/or resolved.” 
 
• 
Premature discontinuation from all treatments and follow-up 
In Section 6.1.2.1.2, new text has been added as follows: “Subjects who prematurely 
discontinue from all treatments, i.e., chemotherapy, IMRT and Debio 1143/matched placebo, in 
the absence of an EFS event, will undergo the EOT visit and then enter the EFS follow-up 
period according to schedule.” 
This new text has been added to be consistent with Table 1-2. 
 
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• 
End of treatment visit (EOT) 
In Section 1.3, new text has been added to specify that EOT visit should be performed prior to 
the start of any subsequent anticancer therapy. 
Radiotherapy Quality Assurance 
To avoid confusion and misunderstanding with the company name of one of the vendors 
(QARC), the wording in Section 6.1.2.3 has been modified as follows: “The RadioTherapy 
Quality Assurance (RT-QA) Review Center (Section 11.2.2) will centrally review the IMRT 
treatment plan(s) to ensure compliance with protocol guidelines and provide feedback to the 
site.” 
The abbreviation QARC has been replaced with RT-QA across all the protocol. 
• 
Head and neck CT-scan 
To avoid misleading interpretation, it has been clarified in Section 8.2.1 that i.v. contrast-
enhanced CT-scan or MRI of head and neck should cover the orbits and 18F-FDG-PET scan 
should be from the skull base to proximal upper legs. 
 
• 
Radiation therapy scheme 
After discussion with several radiation oncologists, the Table 6-3 has been modified replacing 
the technical terminologies “Gross Target Volume (GTV)” and “Clinical Target Volume (CTV)” 
with the most appropriate one “Planning Target Volume (PTV)”. 
 
• 
Central and local laboratory assessments at screening 
To avoid misleading interpretation, the following sentence has been added in Section 8.1 “The 
central laboratory assessments needed for subject eligibility are specified in Table 8-2. Local 
laboratory results only for HBV/HCV/HIV tests and HPV status obtained within 2 weeks before 
ICF signature may be accepted”. 
 
• 
IMRT dosage across the protocol 
After discussion with several radiation oncologists, the GTV was replaced by the PTV and 
consequently, the wording of the IMRT has been modified as follows: “IMRT (70 Gy in 35 
fractions over 7 weeks, 2.0 Gy/fraction, 5 days/7)”. 
 
• 
Blood transfusions 
To avoid misinterpretation, transfusions mentioned in inclusion criterion number 10 were 
clarified as blood transfusions. 
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• 
Definition of eligibility to receive the study treatments 
To avoid misinterpretation between the terms “enrolled” and “eligible”, the text in Section 1.3 
has been modified as follows: “A subject will be considered eligible to receive the study 
treatments after he/she has signed the ICF, all eligibility criteria have been met and the IMRT 
plan has been sent to the Radiotherapy Quality Assurance (RT-QA) Review Center (see 
Section 11.2.2). Randomization can be performed once the subject is considered eligible”. 
Other minor modifications: 
• 
Section 1.3: Study treatment (C1D1) should begin within 7 days after randomization. 
• 
Table 1-3: The visit window of ± 3 days on C2D2 and C3D2 were removed since these 
visits must be done the day after C2D1 and C3D1. 
• 
Throughout the protocol, minor edits, abbreviations, correction of typographical errors and 
formatting were made to improve readability. 
 
 
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13.11. 
Sponsor Signature Page
Study Title:
A randomized, double-blind placebo-controlled, Phase 3
study of Debio 1143 in combination with platinum-based
chemotherapy and standard fractionation intensity-
modulated radiotherapy in patients with locally advanced
squamous cell carcinoma of the head and neck, suitable
for definitive chemoradiotherapy (TrilynX)
Regulatory Agency Identifying EudraCT Number: 2020-000377-25
Numbers:
Clinical Study Protocol Version: V13.0, 18 March 2024, including amendments 1-12.0
Name, academic degree:
Function/TitIe:
Institution:
Address:
General Merck Phone
Number:
General Merck Fax
Number:
Merck, S.L.
Maria de Molina, 40
28006 Madrid, Spain
0034 659797632
Not Applicable
187/189
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13.12. 
Coordinating Investigator Signature Page  
Study Title: 
A randomized, double-blind placebo-controlled, Phase 3 
study of Debio 1143 in combination with platinum-based 
chemotherapy 
and 
standard 
fractionation 
intensity-
modulated radiotherapy in patients with locally advanced 
squamous cell carcinoma of the head and neck, suitable 
for definitive chemoradiotherapy (TrilynX) 
Regulatory Agency Identifying 
Numbers: 
EudraCT Number: 2020-000377-25 
Clinical Study Protocol Version: V13.0, 18 March 2024, including amendments 1-12.0 
I approve the design of the clinical study, am responsible for the conduct of the study at this site 
and understand and will conduct it per the clinical study protocol, any approved protocol 
amendments, ICH GCP (Topic E6) and all applicable Health Authority requirements and national 
____________________________ 
Date of Signature 
 
Name, academic degree: 
 
Function/Title: 
 
Institution: 
  
Address: 
 
Telephone number: 
 
Fax number: 
 
E-mail address: 
 
 
 
 
21.03.2024
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PD
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TrilynX 
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13.13. 
Principal Investigator Signature Page  
Study Title: 
A randomized, double-blind placebo-controlled, Phase 3 study 
of 
Debio 
1143 
in 
combination 
with 
platinum-based 
chemotherapy and standard fractionation intensity-modulated 
radiotherapy in patients with locally advanced squamous cell 
carcinoma of the head and neck, suitable for definitive 
chemoradiotherapy (TrilynX) 
Regulatory Agency 
Identifying Numbers: 
EudraCT Number: 2020-000377-25 
Clinical Study Protocol 
Version: 
V13.0, 18 March 2024, including amendments 1-12.0 
Site Number: 
 
I am responsible for the conduct of the study at this site and understand and will conduct it per the 
clinical study protocol, any approved protocol amendments, ICH GCP (Topic E6) and all applicable 
Health Authority requirements and national laws. 
I also understand that Health Authorities may require the Sponsors of clinical studies to obtain and 
supply details about ownership interests in the Sponsor or Investigational Medicinal Product and 
any other financial ties with the Sponsor. The Sponsor will use any such information solely for 
complying with the regulatory requirements. Therefore, I agree to supply the Sponsor with any 
necessary information regarding ownership interest and financial ties including those of my 
spouse and dependent children, and to provide updates as necessary to meet Health Authority 
requirements. 
____________________________________ 
____________________________ 
Signature 
Date of Signature 
Name, academic degree: 
 
Function/Title: 
 
Institution: 
 
Address: 
 
Telephone number: 
 
Fax number: 
 
E-mail address: 
 
 
CI