A Randomized, Double-blind, Placebo-controlled, 2-arm Phase III Study to Assess Efficacy and Safety of Xevinapant and Radiotherapy Compared to Placebo and Radiotherapy for Demonstrating Improvement of Disease-free Survival in Participants With Resected Squamous Cell Carcinoma of the Head and Neck, Who Are at High Risk for Relapse and Are Ineligible for High-dose Cisplatin (XRAY VISION)
Phase: PHASE3
Conditions: Head and Neck Cancer
Sponsor: EMD Serono Research & Development Institute, Inc.

Xevinapant 
Phase III Xevinapant and Radiotherapy in Resected LA SCCHN, High-Risk, 
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Clinical Study Protocol  
Title Page  
Clinical Study Protocol Title: 
A randomized, double-blind, placebo-controlled, 
2-arm Phase III study to assess efficacy and safety 
of xevinapant and radiotherapy compared to 
placebo and radiotherapy for demonstrating 
improvement 
of 
disease-free 
survival 
in 
participants with resected squamous cell carcinoma 
of the head and neck, who are at high-risk for 
relapse and are ineligible for high-dose cisplatin 
Study Number: 
MS202359_0002 
Protocol Version: 
18 October  2023/Version 6.0 
Merck Compound: 
MSC2735845 (Debio 1143)  
Merck Registered Compound Name in 
Japan: 
Not Applicable 
Study Phase: 
3 
Short Title: 
Phase III xevinapant and radiotherapy in resected 
LA 
SCCHN, 
high-risk, 
cisplatin-ineligible 
participants  
Acronym: 
XRAY VISION 
Coordinating Investigator: 
 
 
  
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Sponsor Name and Legal Registered 
Address: 
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 
Regulatory Agency Identifying 
Numbers: 
FDA Center for Drug Evaluation and Research, 
IND: 156735 
EudraCT: 2022-001144-18 
Keywords 
Adjuvant RT, Stage III, Stage IVA, Stage IVB, oral 
cavity, oropharynx, larynx, hypopharynx, unfit  
Protocol Amendment Summary of Changes 
Protocol History 
Version Number 
Type 
Version Date 
6.0 
Global 
18 October 2023 
5.0 
Global 
25 July 2023 
4.0 
Global 
10 May 2023 
3.0 
Global 
17 August 2022 
2.0 
Global 
28 April 2022 
1.0 
Original Protocol 
23 March 2022 
Protocol Version 6.0 (18 October  2023) 
Overall Rationale for the Amendment 
The main rationale for this protocol amendment is to add 
 
 adverse event of special interest. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities, Table 4 
Added revised text “In case of 
premature treatment discontinuation, 
the FU7 visit should be performed 
according to original schedule. 
Imaging and clinical tumor 
assessments will also follow original 
schedule starting from Month 9.” 
For better clarity 
5.1 Inclusion criteria 
Updated Inclusion criteria #9 
regarding cisplatin ineligibility criteria: 
For US participants with history of 
hearing impairment – added text to 
refer to Appendix 12  
To align with country-specific criteria 
6.5.1.2 Dose 
modification 
xevinapant/ 6.5.2.3 
Treatment interruption 
Addition that if IMRT is interrupted 
due to technical or logistical reasons, 
xevinapant/placebo dosing can 
continue 
In case IMRT is interrupted for technical or 
logistical reasons, xevinapant/placebo 
treatment can continue.  
8.3.7 AESI 
Addition that changes to the AESI list 
will be included in the IB at the regular 
annual update  
To simplify future management of changes to 
the AESI list. 
 
 
 
 
 
 
 
 
Appendix 6 Study 
Governance 
Added paragraph on applicable 
regulations to protect personal data 
Added information to clarify follow-up if 
regulations to protect personal data are not 
followed 
 
 
 
 
  
 
 
Appendix 12 Country-
Specific Requirements 
Updated 5.1 Inclusion Criteria #9 for 
US participants with tinnitus 
As per US FDA feedback 
 
 
  
 
 
 
 
 
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Table of Contents  
Table of Contents  ..............................................................................................................4 
Table of Tables 
 ..............................................................................................................8 
Table of Figures 
 ..............................................................................................................9 
1 
Protocol Summary ..............................................................................10 
1.1 
Synopsis ..............................................................................................10 
1.2 
Schema ................................................................................................12 
1.3 
Schedule of Activities .........................................................................15 
2 
Introduction .........................................................................................30 
2.1 
Study Rationale ...................................................................................30 
2.2 
Background .........................................................................................31 
2.3 
Benefit/Risk Assessment ....................................................................33 
2.3.1 
Risk Assessment .................................................................................34 
2.3.2 
Benefit Assessment .............................................................................36 
2.3.3 
Overall Benefit: Risk Conclusion .......................................................37 
3 
Objectives and Estimands ...................................................................37 
4 
Study Design .......................................................................................39 
4.1 
Overall Design ....................................................................................39 
4.2 
Scientific Rationale for Study Design ................................................41 
4.2.1 
Participant Input into Design ..............................................................44 
4.3 
Justification for Dose ..........................................................................44 
4.4 
End of Study Definition ......................................................................47 
5 
Study Population .................................................................................47 
5.1 
Inclusion Criteria ................................................................................48 
5.2 
Exclusion Criteria ...............................................................................52 
5.3 
Lifestyle Considerations .....................................................................55 
5.3.1 
Meals and Dietary Restrictions ...........................................................55 
5.4 
Screen Failures ....................................................................................55 
5.5 
Criteria for Temporarily Delaying the Randomization/ 
Administration of Study Intervention Administration ........................56 
6 
Study Intervention(s) and Concomitant Therapies .............................56 
6.1 
Study Intervention(s) Administration .................................................56 
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6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability .....................................................................................58 
6.3 
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................59 
6.3.1 
Study Intervention Assignment ..........................................................59 
6.3.2 
Blinding ..............................................................................................59 
6.3.3 
Emergency Unblinding .......................................................................60 
6.4 
Study Intervention Compliance ..........................................................60 
6.5 
Dose Modification ..............................................................................61 
6.5.1 
Xevinapant or Placebo Dosing and Administration ...........................61 
6.5.1.1 
Concurrent Administration to IMRT ..................................................61 
6.5.1.2 
Dose Modification, Interruption and Discontinuation of 
Xevinapant / Placebo Treatment .........................................................62 
6.5.1.3 
End of Xevinapant / Placebo Treatment .............................................68 
6.5.2 
Radiotherapy .......................................................................................68 
6.5.2.1 
General Considerations .......................................................................68 
6.5.2.2 
Treatment ............................................................................................68 
6.5.2.3 
Treatment Interruption ........................................................................70 
6.5.2.4 
Management of Acute “Radiation In-Field” Toxicity ........................70 
6.5.2.5 
End of IMRT .......................................................................................71 
6.6 
Continued Access to Study Intervention After the End of the 
Study ...................................................................................................71 
6.7 
Treatment of Overdose .......................................................................71 
6.8 
Concomitant Therapy .........................................................................71 
6.8.1 
Permitted Medicines ...........................................................................72 
6.8.2 
Medications to be Used with Caution with Xevinapant or Placebo ...72 
6.8.3 
Prohibited Medicines ..........................................................................74 
6.8.3.1 
Recombinant Human Erythropoietin and Derivates ...........................74 
6.8.3.2 
Food and Herbal Preparations ............................................................74 
6.8.3.3 
Inhibitors/Inducers of P-gp .................................................................75 
6.8.3.4 
CYP3A4/5 Narrow Therapeutic Index Drugs or Sensitive 
Substrates ............................................................................................75 
6.8.4 
Other Interventions .............................................................................76 
6.8.4.1 
Nutritional Support .............................................................................76 
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6.8.4.2 
Dental Care .........................................................................................77 
6.8.4.3 
Pain .....................................................................................................77 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...............................................................77 
7.1 
Discontinuation of Study Intervention................................................77 
7.1.1 
Temporary Discontinuation ................................................................78 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................78 
7.3 
Lost to Follow-Up...............................................................................79 
8 
Study Assessments and Procedures ....................................................80 
8.1 
Efficacy Assessments and Procedures ................................................81 
8.1.1 
Radiological Assessment ....................................................................82 
8.1.2 
Clinical Assessment ............................................................................83 
8.1.3 
DFS Events and Definitions ...............................................................83 
8.1.4 
Endpoint Assessment by IRC .............................................................84 
8.1.5 
Quality of Life ....................................................................................85 
8.2 
Safety Assessments and Procedures ...................................................89 
8.2.1 
Physical Examinations ........................................................................89 
8.2.2 
Vital Signs ..........................................................................................89 
8.2.3 
Electrocardiograms .............................................................................90 
8.2.4 
Clinical Safety Laboratory Assessments ............................................91 
8.2.4.1 
HPV Status in Participants with OPC .................................................92 
8.2.5 
External Data Monitoring Committee ................................................93 
8.2.6 
Patient Diary .......................................................................................93 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting ............................................................................................95 
8.3.1 
Method of Detecting Adverse Events and Serious Adverse Events ...95 
8.3.2 
Follow-up of Adverse Events and Serious Adverse Events ...............96 
8.3.3 
Regulatory Reporting Requirements for Serious Adverse Events .....96 
8.3.4 
Pregnancy ...........................................................................................97 
8.3.5 
Cardiovascular and Death Events .......................................................97 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs ................................................................98 
8.3.7 
Adverse Events of Special Interest .....................................................98 
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8.3.7.1 
AESIs During the Treatment Period ...................................................98 
8.3.7.2 
Late Onset AESIs During the Follow-up Period (After FU28 Visit 
up to EOS Visit)..................................................................................99 
8.4 
Pharmacokinetics ................................................................................99 
8.5 
Pharmacogenomics ...........................................................................100 
8.6 
Biomarkers ........................................................................................100 
8.7 
Immunogenicity Assessments ..........................................................101 
8.8 
Medical Resource Utilization and Health Economics ......................101 
9 
Statistical Considerations ..................................................................102 
9.1 
Statistical Hypotheses .......................................................................102 
9.1.1 
Primary Objective DFS .....................................................................102 
9.1.2 
Secondary Objective OS ...................................................................103 
9.2 
Sample Size Determination ..............................................................103 
9.3 
Analyses Sets ....................................................................................106 
9.4 
Statistical Analyses ...........................................................................106 
9.4.1 
Efficacy Analyses .............................................................................106 
9.4.2 
Safety Analyses ................................................................................111 
9.4.3 
Other Analyses ..................................................................................112 
9.4.4 
Sequence of Analyses .......................................................................112 
10 
References .........................................................................................115 
11 
Appendices .......................................................................................120 
Appendix 1 
Abbreviations ....................................................................................121 
Appendix 2 
Clinical Laboratory Tests .................................................................125 
Appendix 3 
Conduct of the Study during the COVID-19 Pandemic ...................127 
Appendix 4 
Contraception and Barrier Requirements .........................................130 
Appendix 5 
G8 Questionnaire ..............................................................................132 
Appendix 6 
Study Governance .............................................................................133 
Appendix 7 
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Applied to Adjuvant Studies of Squamous Cell 
Carcinoma of the Head and Neck .....................................................140 
Appendix 8 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ..............................................144 
Appendix 9 
Recommended Dental/Oral Evaluations ...........................................151 
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Appendix 12 
Country-Specific Requirements ........................................................154 
Appendix 13 
Protocol Amendment History ...........................................................157 
Appendix 14 
Sponsor Signature Page ....................................................................165 
Appendix 15 
Coordinating Investigator Signature Page ........................................166 
Appendix 16 
Principal Investigator Signature Page ...............................................167 
 
Table of Tables  
Table 1 
Schedule of Activities: Screening and Combination Treatment 
Period ..................................................................................................18 
Table 2 
Schedule of Activities: Monotherapy Period ......................................22 
Table 3 
Treatment Diagram and Time Window for Visits ..............................24 
Table 4 
Schedule of Activities: DFS Follow-up Visits ...................................25 
Table 5 
Schedule of Activities: OS Follow-up Visits......................................28 
Table 6 
Schedule of Pharmacokinetic Activities .............................................29 
 
 
 
 
 
 
 
Table 9 
Dose Prescription ................................................................................69 
Table 10 
Anesthetic and Analgesic Drugs to be Used with Xevinapant 
under Close Medical Monitoring ........................................................73 
Table 11 
Other Drugs to be Used with Xevinapant Under Close Medical 
Monitoring ..........................................................................................73 
Table 12 
Examples of Prohibited Inhibitors and Inducers of P-gp with 
Xevinapant / Placebo ..........................................................................75 
Table 13 
Examples of Prohibited CYP3A4/5 Sensitive Substrates with 
Xevinapant ..........................................................................................76 
 
 
Table 15 
ECG Collection Plan ...........................................................................90 
Table 16 
Assessments to be Performed by a Central Laboratory or by a 
Local Laboratory According to Study Visit .......................................92 
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Table 19 
Further Details on Statistical Analysis of Efficacy Estimands 
Beyond Estimands Attribute Specifications in Section 3 .................107 
Table 20 
Statistical Analysis Methods for Safety Endpoints ..........................111 
Table 21 
Planned Efficacy Analyses and Expected Timing ............................112 
 
 
 
Table of Figures  
Figure 1 
Study Diagram ....................................................................................13 
Figure 2 
Study Flow Chart ................................................................................14 
Figure 3 
Milestone Markers ..............................................................................41 
 
 
 
 
 
 
 
 
Figure 6 
Fixed-Sequence Strategy to Control FWER at 2.5% 1-Sided, 
where the Arrows Indicate the Alpha Reallocation Applied if the 
Originating Test Rejects its Null Hypothesis Otherwise 
Confirmatory Testing is Discontinued ..............................................113 
 
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Brief Summary: The purpose of this study is to demonstrate the superior efficacy of xevinapant 
vs placebo when added to radiotherapy in the treatment of high-risk participants with resected LA 
SCCHN who are ineligible to receive cisplatin-based chemoradiation concurrently. 
Study details include: 
• Study duration: Participants will be followed until the last on-study participant reaches his/her 
60-month post-randomization visit, a decision to end the study has been triggered, or until 
premature discontinuation from study, whichever occurs first. 
• Treatment duration: 18 weeks, consisting of six 3-week cycles. 
• Health measurement/observation: Improved Disease-Free Survival. 
• Visit frequency: Weekly visit during combination therapy period, once every 3 weeks during 
monotherapy period, and every 3, 4, or 6 months during the Disease-Free Survival Follow-up 
period in Year 1, 2 and 3, or 4 and 5 (with telephone contact in between), respectively, and 
every 3 months (telephone visits allowed) during the Overall Survival Follow-up period. 
Xevinapant is not available through an expanded access program. 
Number of Participants: A total of approximately 700 participants will be randomly assigned to 
study intervention. It is anticipated to conduct the study in the US, Canada, Europe, Latin America, 
and Asia-Pacific. 
Study Intervention Groups and Duration: Participants who meet the eligibility criteria will be 
enrolled and randomized in a 1:1 ratio, using permuted block allocation to Arm A or Arm B and 
will receive the following treatments: 
• Arm A: 3 cycles of xevinapant (oral solution 200 mg/day from Day 1 to 14, per 3-week cycle) 
+ IMRT (66 Gy in 33 fractions, 2 Gy/fraction, 5 days/week), followed by 3 cycles of 
monotherapy of xevinapant (oral solution 200 mg/day from Day 1 to 14, per 3-week cycle) 
OR 
• Arm B: 3 cycles of placebo (matching oral solution from Day 1 to 14, per 3-week cycle) + 
IMRT (66 Gy in 33 fractions, 2 Gy/fraction, 5 days/week), followed by 3 cycles of monotherapy 
of placebo (matching oral solution from Day 1 to 14, per 3-week cycle). 
Involvement of Special Committee(s): Yes 
1.2 
Schema  
The overall study design is summarized in Figure 1. 
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Figure 1 
Study Diagram  
 
 
D = day, DFS = disease-free survival, IMRT = intensity modulated radiation therapy, M = Month, OS = overall 
survival, R = randomization 
a 
Each cycle consists of 3 weeks. 
b 
DFS Follow-up period starts after EOT visit and runs until Month 60 after randomization. 
The study flow chart is shown in Figure 2. 
Note: For a detailed overview of all visits, assessments and visit windows, see Table 1, Table 2, 
Table 3, Table 4, and Table 5. 
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Figure 2 
Study Flow Chart  
 
CRT=chemoradiotherapy, EOS=end of study, EOT=end of treatment, DFS=disease-free survival, HPV=human 
papilloma virus, HRQL=health-related quality of life, IMRT=intensity modulated radiation therapy, LA SCCHN=locally 
advanced squamous cell carcinoma of the head and neck, OS=overall survival, Q3W=every 3 weeks. 
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1.3 
Schedule of Activities  
The schedule of the completion of the study visits/procedures is presented in Table 1, Table 2, 
Table 3, Table 4, and Table 5. 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 ICF and can last up to 28 days 
until randomization. 
IV 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, if 
required, HIV test, and fiberoptic endoscopy, if appropriate, performed within 2 weeks before ICF 
signature do not have to be repeated during screening. 
If several IV 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 imaging modality must be used throughout the study. Further details 
on imaging are provided in Table 1, Table 2, Table 4, and Section 8.1. 
In addition, the most recent pre-surgery diagnostic/staging CT and/or MRI scans done as a part of 
SoC should be submitted to the IRC vendor, if available, as well as any recent pre-surgery or 
baseline PET-CT scan if acquired, to facilitate IRC assessment of any potential macroscopic 
residual disease at baseline. If biopsy has been performed during screening to exclude presence of 
residual disease, upon IRC request biopsy reports may be presented to the IRC. 
During Screening, results from a central laboratory, including a pregnancy test, should be used to 
define participant eligibility. The following tests may be obtained locally: HIV test within 2 weeks 
before ICF signature, HPV status by p16 IHC (Section 8.2.4.1), SARS-CoV-2 PCR and/or antigen 
test if required, and retest of laboratory abnormalities during the Screening period (Section 8.2.4). 
After randomization, laboratory assessments should be performed by a central laboratory 
designated by the Sponsor, except for the safety laboratory assessments to confirm eligibility for 
treatment on CxD1 and pregnancy tests, which may be obtained locally, and except for the 
urinalysis dipstick tests on CxD1, which will be done locally (Section 8.2.4). 
A participant will be considered as eligible to receive the study interventions after he/she has 
signed the ICF, and all eligibility criteria have been met. Randomization can be performed once 
the participant is eligible, and C1D1 should be within 3 days after randomization. Study 
intervention administration starts after randomization, with combination treatment on C1D1. The 
IMRT plan must be approved by the RT-QA Review Center prior to the start of the IMRT. 
Study procedures must be performed according to the planned visit schedule within the permitted 
visit windows. Study procedures of the C1D1 visit have a visit window of – 3 days unless they are 
required to be performed on first dosing day (C1D1). Other CxD1 visits have a visit window of ± 
3 days. During the treatment period, each study visit day and allowed time window will be based 
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on the C1D1 date. The treatment diagram and time windows for visits during the treatment period 
are presented in Table 3. 
The EOT visit will be performed 14 days (± 7 days) after last study intervention administration 
(i.e. xevinapant/placebo, or IMRT, whichever is administered last) or 14 days (± 7 days) after 
premature discontinuation during treatment but prior to the start of any subsequent anticancer 
therapy. 
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 intervention or withdrawal 
from the study due to reasons described in Section 7. 
The DFS follow-up period will start after the EOT visit. The DFS follow-up period must be 
performed according to the planned visit schedule within the permitted visit windows. Day 1 of 
study month corresponds to the calendar day of C1D1. In case of premature discontinuation of 
study intervention (e.g. unacceptable toxicity), efficacy assessments will continue according to 
original schedule until confirmed disease relapse (Section 8), regardless of start of subsequent 
anticancer treatment. Participants with confirmed disease relapse will enter the OS follow-up 
period at time of the confirmation of the event and will be followed up for survival status at least 
every 3 months, until the EOS (Section 4.4). Survival follow-up can be performed by telephone 
calls, unless the participant has entered the OS follow-up period earlier than 28 months after start 
of treatment (e.g. due to PD). In this case, clinic visits are required up to 28 months after start of 
treatment or until start of next line of anticancer therapy, whichever occurs earlier. 
During the DFS follow-up period and OS follow-up period, each study visit day and allowed time 
window will be based on the C1D1 date. 
After completion of the OS follow-up period, participants who have not discontinued the study 
prematurely will undergo the EOS assessments (scheduled date of the Month 60 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 starts the OS follow-up (60 months after randomization), the 
participant’s EOS visit will be performed at the same time as the Month 60 visit. In case of 
premature discontinuation from the study, the participant’s EOS visit will be performed when the 
participant discontinues from the study. 
The EOS visit can be performed by telephone call. 
The following schedules of activities and assessments are presented: 
Table 1: Screening and Combination Treatment Period 
Table 2: Monotherapy Period 
Table 3: Treatment Diagram and Time Windows for Visits 
Table 4: DFS Follow-up Visits 
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Table 5: OS Follow-up Visits 
Table 6: Schedule of Pharmacokinetic Activities
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Table 3 
Treatment Diagram and Time Window for Visits  
 
C=cycle, EOT=end of treatment, IMRT=intensity modulated radiation therapy, W=week. 
a 
On days when IMRT is to be administered, xevinapant / placebo must be administered before IMRT. 
b 
During the treatment period, each study visit day and allowed time windows will be based on the C1D1 date. C1D1 is triggered by the 1st dose administration 
of xevinapant / placebo. Crossed gray boxes in the row “Time Window for Visit” represent days around a specific study visit (represented by solid black boxes 
in the row “Study visit day”) where the visit can be rescheduled (see also time windows planned in the SoA, Table 1 and Table 2). 
c 
Xevinapant / placebo (Section 6.5.1): once daily from D1 to D14 of each cycle (solid red boxes). Xevinapant / placebo should be administered orally, in the 
morning, preferable 1 to 4 hours before IMRT. 
d 
IMRT should be delivered in 33 fractions over 6.5 weeks, 5 fractions weekly (solid yellow boxes). If IMRT is put on hold due to safety or administrative 
reason, the 6.5 weeks of IMRT can be administered until Study Week 9 (striped yellow boxes) (Section 6.5.2). 
e 
The EOT visit will be performed 14 days (± 7 days) after last study treatment administration (i.e. xevinapant / placebo, or IMRT whichever is administered 
last) or 14 days (±7 days) after premature discontinuation during treatment, but prior to start of any subsequent anticancer therapy. 
 
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Table 6 
Schedule of Pharmacokinetic Activities  
Treatment 
Day 
Timepoint of  
Xevinapant PK Sampling  
Notes 
C1D1 
0.5-4 h postdose xevinapant/placebo b 
On C1D1, C1D2, C1D8, C2D2, C2D8, 
participants must be at the clinical unit 
before xevinapant/placebo is administered 
to ensure PK blood sample collection as 
per Schedule of Activities. The time of dose 
on those days and time of the draw for PK 
assessment must be reported in the eCRF. 
In addition, time of last dose prior to 
xevinapant PK collection (i.e. at C1D7, 
C2D1, C2D7) needs to be recorded in the 
participant’s diary and reported in the 
eCRF.  
C1D2 
Predose xevinapant/placebo  
C1D8 
Predose xevinapant/placebo b 
and 0.5-4 h postdose xevinapant/placebo b 
C2D2 
Predose xevinapant/placebo  
C2D8 
Predose xevinapant/placebo  
and 0.5-4 h postdose xevinapant/placebo 
C3D8a 
At time of blood hematology/ 
biochemistry laboratory assessments 
On C3D8, xevinapant/ placebo dose is 
encouraged to be taken at home and the 
time of the last dose prior to PK sample on 
that day is recorded by participant in the 
diary and reported in the eCRF. The time 
of the draw for PK assessment must be 
reported in the eCRF 
C4D1 
2-4 h postdose xevinapant/placebo 
On C4D1, C5D1, and C6D1 Dose is taken 
at the hospital. The time of the oral dose 
and draw for PK assessment must be 
reported in the eCRF. 
C5D1 
2-4 h postdose xevinapant/placebo 
C6D1 
2-4 h postdose xevinapant/placebo 
CxDx=Cycle x Day x, eCRF=electronic case report form, PK=pharmacokinetics. 
Predose sample is taken within 1 hour prior to dosing 
a 
Participants are encouraged to take xevinapant / placebo at home prior to hospital visit at C3D8. 
b 
PK samples at C1D1 (post dose) C1D8 (predose and postdose) are taken after the ECG assessment at the 
corresponding time point (see Table 15, Section 8.2.3). 
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2 
Introduction  
Xevinapant is a novel, orally available antagonist of IAPs that promotes cancer cell death via 
apoptosis. Xevinapant fosters antitumor immunity and potentially sensitizes tumor cells for 
various cytotoxic therapies, including chemotherapy, radiotherapy and/or immunotherapy (Serova 
2014, Matzinger 2015, Tao 2019). 
Nonclinical data suggest xevinapant activity in SCCHN models when combined with radiation as 
shown by Matzinger (2015). The value of adding xevinapant to conventional cisplatin-based 
chemoradiotherapy in the treatment of previously untreated patients with unresected LA SCCHN 
was recently confirmed in a Phase II study (Sun 2020). 
This study aims to confirm the value of adding xevinapant to the treatment of resected locally 
advanced SCCHN patients with a high-risk of relapse who are ineligible to receive cisplatin-based 
chemoradiotherapy and who are often treated with radiotherapy. 
Detailed information on the chemistry, pharmacology, efficacy, and safety of xevinapant is in the 
IB. 
2.1 
Study Rationale  
The purpose of this study is to demonstrate the superior efficacy of xevinapant vs placebo when 
added to radiotherapy in the treatment of participants with resected LA SCCHN who are at 
high-risk for relapse and are ineligible to receive cisplatin-based CRT. 
SCCHN is the 7th most common cancer worldwide with an annual incidence of approximately 
700,000 and a mortality estimated at 350,000 in 2018 (Bray 2018). The majority of SCCHN 
patients are diagnosed with locoregional disease, in which RT concurrent with high-dose cisplatin 
was identified as most effective and thus preferred treatment of choice (NCCN v3 2021). 
Concomitant chemoradiotherapy has also been established as a SoC for resected patients with a 
high-risk (due to extra-capsular extension and/or positive margin) of relapse after surgery (Bernier 
2004, Cooper 2004, NCCN v3 2021, Machiels 2020). However, a large proportion of these patients 
are not suitable for standard of care treatment with high-dose cisplatin-based CT concomitant to 
RT, either due to their age or to their medical/general condition and/or comorbidities (Harari 2014). 
So, improving the outcome of these patients defines an important unmet clinical need. 
Xevinapant is an antagonist of IAPs that has been shown in nonclinical in vitro and in vivo models 
to have both chemo- and radiosensitizing potential, as well as immunomodulatory potential 
(Serova 2014, Matzinger 2015, Tao 2019). In unresectable LA SCCHN patients, the addition of 
xevinapant to SoC CRT recently showed a statistically significant and clinically meaningful 
improvement in locoregional control at 18 months compared to placebo and SoC alone (Sun 2020). 
Following the 36-month analysis, OS and PFS also showed a clinically meaningful improved 
benefit from xevinapant versus placebo. In the current study concept, the addition of xevinapant 
to the SoC regimen of radiotherapy is anticipated to further sensitize SCCHN tumors to the effects 
of radiotherapy. 
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The current Phase III study aims to support the approval of xevinapant in combination with 
radiotherapy for the treatment of high-risk participants with resected LA SCCHN who are 
ineligible to receive standard cisplatin-based chemoradiation concurrently. 
2.2 
Background  
Head and neck carcinoma include a variety of epithelial tumors originating in the lip, oral cavity, 
hypopharynx, oropharynx, nasopharynx, or larynx. Head and neck cancers are the 7th most 
common cancer worldwide with an annual incidence of approximately 700,000 and a mortality 
estimated at 350,000 in 2018 (Bray 2018). In the US alone, 50,000 new cases and 10,000 deaths 
are reported annually, while in Europe, 140,000 new cases are reported annually (Iglesias 
Docampo 2018). A vast majority of these cancers (90% to 95%) are SCCHN which are closely 
associated with alcohol and tobacco use. SCCHN of the oropharynx is also associated with HPV, 
essentially type 16 infection. Approximately two-third of patients are diagnosed as LA SCCHN 
(Denaro 2016). 
Multidisciplinary treatments, including surgery, RT and chemotherapy alone or in combination 
represent the treatment options for SCCHN patients depending on the disease stage. Locally 
advanced disease is treated with curative intent and requires multimodal approaches including 
combined CRT either as adjuvant therapy after tumor resection or as definitive curatively intended 
treatment. 
For resected patients with a high-risk of relapse after surgery, due to extra-capsular extension 
and/or positive margin, adjuvant concomitant chemoradiotherapy (CT-RT) of 66 Gy / 6.5 weeks 
with concomitant 100 mg/m² cisplatin x 3 cycles has been established as a standard of care (SoC) 
(Bernier 2004, Cooper 2004, NCCN v3 2021, Machiels 2020). 
However, cisplatin is associated with both acute and late, often irreversible toxicities, which are 
manifested as detrimental short- and long-term complications for patients and result in low 
treatment adherence and nonoptimal treatment for many patients (Porceddu 2020). In addition, a 
large proportion of these high-risk patients are not suitable or unfit for receiving cisplatin, due to 
age and comorbidities but also due to slow recovery and/or complications after surgery (Harari 
2014). 
Treatment guidelines across Europe and the USA recommend RT as an alternative approach for 
resected LA SCCHN in patients ineligible to receive cisplatin (NCCN v3 2021, Machiels 2020). 
The failure rate of RT alone is high and higher than in the corresponding resected high-risk LA 
SCCHN patients who are able to receive cisplatin (Bernier 2004, Cooper 2004). Improving the 
outcome of these cisplatin-unfit patients defines an important unmet clinical need to find more 
efficient and better tolerated therapies. 
Due to the pivotal role of RT in many LA SCCHN settings, a lot of focus is being put on research 
into safe and powerful radiosensitizing agents. In addition, resistance of tumor cells to apoptosis 
is a major problem in current cancer treatment. Therefore, further development of new molecular 
anticancer therapies that specifically target resistance of cancer cells to apoptosis is warranted 
(Nicholson 2000). 
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IAPs are key endogenous inhibitors of apoptosis, and overexpression of these proteins was 
detected in numerous cancers, including SCCHN. IAPs have also been shown to interfere with the 
efficacy of RT (Tamm 2000). 
Xevinapant is an antagonist of IAPs with chemosensitizing, radiosensitizing, and 
immunomodulatory activities. Nonclinical studies in several in vitro and in vivo SCCHN models 
demonstrated an efficient antiproliferative activity and a synergistic enhancement of intrinsic 
cellular radiation sensitivity when xevinapant was combined with RT. The synergistic effect of 
xevinapant combined with RT in vivo was able to cure tumors in 8 of 10 xenografted mice without 
any apparent toxicity whereas all mice died with RT alone (Matzinger 2015). These results indicate 
that xevinapant in combination with RT has a promising therapeutic potential in the treatment of 
SCCHN. 
Based on current understanding of mechanisms of action, the value of adding xevinapant to 
platinum-based conventional CRT in previously untreated patients with unresected LA SCCHN 
has been investigated in a Phase I/II study (Debio 1143-201) and its findings are currently being 
confirmed in a Phase III study (Debio 1143-301 [TrilynX], MS202350_006). Efficacy results from 
the 2-year primary analysis from Study Debio 1143-201 have shown antitumor activity of 
xevinapant: participants treated with xevinapant were around 2.5 times more likely to have LRC 
18 months after completing treatment, compared with participants having received a placebo. A 
significant improvement was confirmed at 3 years and xevinapant was found superior to placebo 
for LRC, PFS, and OS (Bourhis 2020). Overall, the safety profile of xevinapant, when added to 
high-dose cisplatin and concurrent RT (CRT), was predictable and manageable, and did not 
jeopardize the delivery of high-dose cisplatin concurrent with standard fractionation RT. 
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 participants’ QOL must be one of the priorities in advancing LA SCCHN 
therapy. 
 
 
 
 Despite this 
significant unmet need, prospective assessments of HRQL in SCCHN are scarce and cross-study 
comparability to inform treatment decisions is limited by heterogeneity in QOL research methods 
(Ojo 2012). 
This Phase III study aims to confirm the value of xevinapant in the treatment of resected LA 
SCCHN participants who are ineligible to receive standard cisplatin-based CRT without 
compromising their health-related quality of life. The nonclinical activity of xevinapant in 
combination with RT in SCCHN models and the primary analysis results of the Debio 1143-201 
study, justifies the clinical investigation of xevinapant in resected SCCHN patients, ineligible to 
receive high-dose cisplatin when added to SoC of RT. 
Refer to the IB for further details on other non-LA SCCHN Phase I studies and on Study Debio 
1143-201. 
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2.3 
Benefit/Risk Assessment  
As of 31 July 2021, a total of 486 participants with a malignancy have been included and exposed 
to study treatment (including placebo or CT alone) in studies with xevinapant, of which 105 had 
received at least 1 blinded dose of xevinapant (200 mg/day, D1 to 14, every 3 weeks) / placebo in 
combination with CRT and 314 have received at least 1 dose of xevinapant. Of these, 64 
participants had received xevinapant as single agent, 150 received xevinapant in combination with 
CT or CRT, and 100 in combination with immunotherapy. 60 participants received placebo in 
combination with CT or CRT. 7 patients were included in the cisplatin only arm of Study Debio 
1143-SCCHN-202 and were not exposed to xevinapant. 
Among the 314 participants with malignancies who had been exposed to xevinapant in scope of 
the Phase I and II 
 
 
 
 
 
Based on the safety data of the Phase I and Phase II studies, xevinapant doses of up to 
mg/day 
were safely combined with either CT or CRT. When used in combination with CT or concomitant 
CRT, xevinapant appears to be equally well tolerated as CT or CRT alone with respect to Grade 
≥ 3 events and TEAEs leading to discontinuation of any of the study treatments and is not 
associated with an increased frequency of drug-related treatment discontinuation. Data from the 
placebo-controlled Study Debio 1143-201, where xevinapant or placebo were administered in 
association with cisplatin and RT, showed an increased risk of mucosal inflammation, dysphagia, 
weight decrease, radiation skin injury, nausea, tinnitus, vomiting and ALT increase in the 
xevinapant arm. Dysphagia, mucositis, and anemia were the most common TEAEs, and more 
frequently manifested as any grade and Grade 3 in the xevinapant group than in the placebo group. 
Except for Grade 1/2 tinnitus and anemia, treatment with xevinapant was not associated with an 
increase in other cisplatin-related AEs, such as renal insufficiency, febrile neutropenia, 
thrombocytopenia, peripheral sensory neuropathy, or severe vomiting. 
RT can cause dermatitis, dry skin, dry mouth, mucositis, alopecia, muscle and joint stiffness, 
diarrhea, dysphagia, anorexia, and fatigue. 
When combining xevinapant with RT, overlapping toxicities are anticipated. 
 
 
 Further, blood count and biochemistry 
must be regularly investigated for changes and weight must be controlled. Appropriate measures 
such as monitoring, dose modification schemes and adequate eligibility criteria have been 
implemented in the protocol (Section 2.3.1) and the anticipated risks are considered manageable. 
In summary, based on current available efficacy and safety data available for xevinapant treatment, 
including the combination with CRT and/or immunotherapy, and for RT alone, the benefit/risk 
assessment for a study combining xevinapant with RT is expected to be positive. 
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For additional considerations regarding the benefit/risk assessment during the COVID-19 
pandemic, refer to Appendix 3. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of xevinapant may be found in Section 4.2 and the IB. 
Based on the available nonclinical and clinical data to date, the conduct of the study, as specified 
in this protocol, is considered justifiable. 
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Eligibility criteria will address the potential risks of QT prolongation and reactivation of latent 
HIV infection or impaired clearance of HBV/HCV chronic infections. Recommendations for the 
use of medications that prolong the QT interval is provided. Caution should be exercised when 
using xevinapant with drugs having a known risk of QTc prolongation. Xevinapant / placebo 
should be permanently discontinued in case of torsade de pointe or signs / symptoms of serious 
arrhythmia (Section 6.5.1.2 and 6.8.2). 
Despite the chemo-radiosensitizing effect of xevinapant it was shown in the Phase II Study Debio 
1143-201 (combining xevinapant and CRT) that TEAEs usually associated with CRT (e.g 
radiation injury, mucositis, dysphagia, anemia) were manageable with dose modifications and 
supportive care and did not compromise the delivery of anticancer treatment given with curative 
intent. 
Pregnant and lactating women will be excluded, and WOCBP will have to use highly effective 
contraception (Appendix 4). 
In conclusion, the toxicities of xevinapant in combination with RT are deemed to be predictable 
and manageable. Participants will be monitored for signs and symptoms and managed accordingly 
in line with current practices/guideline and specific recommendations made in this protocol. 
Adequate hematologic/liver function should be confirmed prior to initiation of treatment. 
Laboratory values and clinical signs or symptoms of toxicities should be closely monitored to 
allow for early identification and intervention. 
2.3.2 
Benefit Assessment  
The clinical proof of concept of xevinapant in patients with unresectable LA SCCHN has been 
demonstrated by the Phase II Study Debio 1143-201. Based on the potential for xevinapant to act 
as a chemo, immune- and/or radiosensitizer, 
 
 
 
 
 
Xevinapant administered in combination with cisplatin-based CRT in participants with LA 
SCCHN (Study Debio 1143-201) reached the primary objective for LRC at 18 months and showed 
clinically and statistically meaningful differences in terms of LRC and PFS, as well as a trend 
toward improved OS. The 24-month analysis of Study Debio 1143-201 demonstrated that the odds 
for LRC at 18 months after completing treatment is 2.5 times higher in participants treated with 
xevinapant compared with participants having received a placebo (odds ratio 2.74; 95% CI: 
1.15;6.53, p=0.0232). In addition, a risk reduction of 63% for progression or death was observed 
in participants treated with xevinapant compared with participants having received a placebo, 
suggesting a clinically significant improvement in PFS (hazard ratio 0.37; 95% CI: 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 the placebo arm. Median PFS was not reached in the xevinapant arm at the 24-month analysis 
cut-off. Results for OS showed the same trend in favor of the xevinapant arm (hazard ratio 0.65; 
95% CI: 0.32;1.33). At the 3-year follow-up, this trend was more pronounced. The probability of 
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Objectives 
Estimands  
Ref. # 
To describe patient-reported 
outcomes over time. 
Endpoints: EORTC QLQ-C30 and HN35, PGIS, PGIC,  
PRO CTCAE  
9 
CRT=chemoradiotherapy
 DFS=disease-free survival, EORTC=European 
Organization for Research and Treatment of Cancer, HRQOL= health-related quality of life, LA SCCHN=locally 
advanced squamous cell carcinoma of the head and neck, OS=overall survival, PGIC=Patient Global Impression of 
Change, PGIS=Patient Global Impression of Severity Scale, PRO CTCAE=Patient-Reported Outcomes Version of 
the Common Terminology Criteria for Adverse Events, QOL=quality of life, RT=radiotherapy, VAS=visual analog 
scale. 
4 
Study Design  
4.1 
Overall Design  
Study Design 
Phase III, parallel-group 
Control Method 
Placebo-controlled 
Single or Multicenter 
Multicenter 
Control Group 
Radiotherapy and placebo 
Study Population Type 
Patients with resected LA SCCHN with high-risk of relapse who 
are ineligible for treatment with cisplatin 
Level and Method of 
Blinding 
Double-blind, matching placebo for xevinapant 
Bias Minimalization 
Method(s) 
Study intervention assignment/ randomization via IWRS. Study 
will be double-blind. 
Study Intervention 
Assignment Method 
Randomization and stratification via IWRS. 
 
 
 
 
 
 
 
 
 
 
 
 
Total Duration of Study 
Participation per Participant 
The study includes the screening period (≤ 28 days), the 
treatment period (combination therapy period followed by the 
monotherapy period, each consisting of 3 cycles), the disease-
free follow-up period (DFS follow-up) and the OS follow-up 
period. Each treatment cycle consists of 3 weeks. Participants 
will be followed up until the last on-study participant reaches 
his/her 60-month post-randomization visit or until premature 
discontinuation from study, whichever occurs first. 
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Provisions for Study 
Extension or Entry into 
Roll-Over Studies 
Not applicable 
Adaptive Aspects of Study 
Design 
Not applicable 
This is a multicenter, randomized double-blind, placebo-controlled, 2-arm, parallel-group Phase 
III study comparing the efficacy and safety of xevinapant versus matched placebo, when 
administered in combination with standard fractionation IMRT in participants with LA SCCHN 
histologically confirmed, previously treated by surgery with high risk of relapse, who are unfit to 
receive cisplatin. The study is designed with the primary objective of demonstrating that treatment 
with xevinapant in combination with postoperative RT (xevinapant arm – Arm A) is superior to 
postoperative RT plus placebo (placebo arm – Arm B) (Figure 1) in terms of DFS. 
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 permuted block allocation to Arm A or Arm B 
and will receive the following treatments: 
• Arm A: 3 cycles of xevinapant (oral solution 200 mg/day from Day 1 to 14, per 3-week cycle) 
+ IMRT (66 Gy in 33 fractions, 2 Gy/fraction, 5 days/week), followed by 3 cycles of 
monotherapy of xevinapant (200 mg/day from Day 1 to 14, per 3-week cycle). 
OR 
• Arm B: 3 cycles of placebo (matching oral solution from Day 1 to 14, per 3-week cycle) + 
IMRT (66 Gy in 33 fractions, 2 Gy/fraction, 5 days/week), followed by 3 cycles of monotherapy 
of placebo (from Day 1 to 14, per 3-week cycle). 
The schedule of concurrent administration of xevinapant/ placebo and IMRT is presented in the 
SoA (Table 1 and Table 2) and the treatment diagram (Table 3). 
It is planned to randomize approximately 700 adult participants of all sexes. The stratification 
factors for the randomization are listed above. 
The primary analysis is planned when approximately 409 DFS events have occurred (Figure 3). If 
the study’s primary objective is met, an alpha-controlled supplementary DFS analysis will be 
conducted. If both DFS tests reject their null hypothesis, the key secondary endpoint OS is tested 
in up to 3 analyses with a primary analysis when the planned number of events are reached (Section 
9.4.4) or the last on-study participant reaches the 60-month post-randomization visit, whichever 
happens first. 
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Figure 3 
Milestone Markers  
 
DFS=disease-free survival, IA=interim analysis, OS=overall survival. 
a 
See Section 9.4.4 for planned OS events at each interim analysis. 
b 
OS primary analysis will be performed when the predefined number of OS events occurred (see Section 9.4.4) 
or after 60-month follow-up for last on-study participant. 
4.2 
Scientific Rationale for Study Design  
Target Population: Resected LA SCCHN, High-risk, Cisplatin-ineligible 
The target population chosen for the study are patients who are expected to significantly benefit 
from treatment with xevinapant combined with RT, being one of the alternative approaches for 
cisplatin-ineligible patients in the postoperative setting with a high risk of relapse. In the current 
study, the high-risk status is defined by the presence after resection of nodal extra-capsular 
extension (ECE) and/or positive resection margins (R1 or close margin ≤ 1 mm). Participants 
should not have any macroscopic residual disease (R2), all gross tumor must have been removed 
by resection, and only a microscopically close margin ≤ 1 mm or microscopically positive margin 
(R1) on the final resection pathology report are permitted. Participants with R2 resection are 
excluded from the study. 
The SoC for postoperative setting in patient at high risk of relapse, is the concurrent use of cisplatin 
(100 mg/m2 once every 3 weeks) with RT (total dose of 66 Gy). However, the positive effect of 
adding cisplatin CT to radiation in the high-risk setting is modest and is accompanied by significant 
incremental toxicity (including ototoxicity, nephrotoxicity, neutropenia, nausea). Also, numerous 
patients do not tolerate and cannot successfully complete the regimen of 100 mg/m2 cisplatin every 
3 weeks during radiation (Cooper 2004, Bernier 2004, Pignon 2009). In addition, many high-risk 
resected LA SCCHN patients are not considered good candidates for high-dose cisplatin because 
of advanced age, renal insufficiency, auditory dysfunction, and/or poor performance status (Harari 
2014). Therefore, improving the outcome of high-risk resected LA SCCHN patients unfit to 
receive cisplatin defines an important unmet clinical need. 
In this study, ‘cisplatin-ineligible’ is defined as a combination of the contraindications or warnings 
of cisplatin as specified in the product information (renal impairment, hearing loss, peripheral 
neuropathy) (Section 5.1):  
• The proposed upper limit of 60 ml/min creatinine clearance is based on relevant publications 
mentioning a creatinine clearance of 50 ml/min as absolute contraindication for high-dose 
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cisplatin and clearances of 50 to 59 ml/min as relative contraindication with a high risk for renal 
toxicity by cisplatin. Hence, cautious treatment with lower doses of cisplatin may be considered 
based on Investigator judgment (Ahn 2016, Porceddu 2020), which is aligned with some EU 
Product Information documents in countries participating in this global phase III study. In order 
to reflect this clinical practice, participants with an eGFR of 50 to 59 ml/min are not 
automatically excluded from the study (Inclusion criteria #9 and #10). 
• Patients with a Grade ≥ 2 audiometric hearing loss or Grade ≥ 2 tinnitus should not receive 
cisplatin (Ahn 2016) and are therefore considered cisplatin-ineligible (Inclusion criterion #9). 
Patients with pre-existing hearing loss treated with cisplatin are at higher risk of suffering from 
deafness at a later time (Vermorken 1983). 
• Participants with peripheral neuropathy Grade ≥ 2 are most at risk of cisplatin toxicity, while 
Grade 3 neuropathy is an absolute contraindication for high-dose cisplatin (Inclusion criterion 
# 9) ( Alvarado-Munoz 2021). 
• Elderly patients may be more susceptible to both nephrotoxicity and peripheral neuropathy 
(refer to cisplatin product information). Advanced age (≥ 70 years) in combination with a poor 
geriatric score, based on the G8 questionnaire (Score ≤ 14), a validated geriatric screening tool 
(Bellera 2012),)  used as an additional criterion to define ineligibility to cisplatin (Appendix 5). 
Target Population: HPV-negative OPC and HPV-positive OPC With Worst Prognosis 
SCCHN of the oropharynx is also associated with HPV, essentially type 16 infection. HPV-
negative OPC patients do have a worse prognosis and require more and better tailored options to 
improve overall treatment outcome (Marur 2014, Du 2019). Although HPV-positive OPC patients 
generally have a better outcome (Perri 2020), HPV-positive advanced stage cancers in heavy 
smokers are still associated with a poor outcome (Chen 2020, Horwich 2021). Therefore, in this 
study only OPC participants with poor prognosis are eligible, i.e. HPV-negative OPC or HPV-
positive OPC participants who are heavy smokers. 
 
 
 
 
 
 
 
 
 
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Double-blind Design 
This study will use a randomized, double-blind design. To maintain the scientific integrity of the 
study, the Investigator, the participant and Sponsor/CRO study personnel will remain blinded to 
the treatment allocation. For the purposes of data presentation to the external DMC, study 
independent personnel may be unblinded to the study data (for further details see Section 6.3.2). 
Randomization is expected to compensate for possible inconsistencies in local assessments, hence 
minimizing any associated bias. 
Endpoints 
The primary endpoint of the study is DFS, an accepted endpoint in resectable SCCHN studies, that 
was shown to be a surrogate endpoint for OS in studies using adjuvant chemoradiotherapy, both 
at the individual and study level (Michiels 2009). The authors showed a strong correlation between 
OS and DFS (correlation coefficient of 0.82 [95% CI: 0.82;0.82] for adjuvant CRT) and a strong 
correlation of the treatment effect between DFS and OS (correlation coefficient of 0.93 [95% CI: 
0.85;1.01] for adjuvant CRT), confirming it as a robust surrogate for OS to assess the treatment 
effect of CRT in randomized studies. DFS will be evaluated by the investigator using imaging and 
clinical review. 
 
 
 
DFS as assessed 
by IRC will be used in an alpha-controlled supplementary analysis, if the main analysis yielded a 
significant treatment arm difference for DFS. The IRC will independently assess both imaging and 
histopathology data. OS as key secondary endpoint is tested for superiority in a group-sequential 
design, if both tests for DFS are significant. The other endpoints are secondary endpoints, 
consistently reported in most large-scale randomized studies for this type of cancer, i.e. time to 
subsequent cancer therapy, adverse events, and QOL. Exploratory objectives include the potential 
prognostic and predictive or prognostic value of candidate biomarkers. 
PROs 
HRQOL can be adversely impacted by SCCHN due to several complications due to treatment and 
symptoms of disease (Liao 2019). Nonsurgical treatments, especially platinum-based CRT, are 
extremely difficult for patients to endure, due to extensive negative side effects (Oun 2018). Thus, 
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improvement in therapy to enhance treatment outcomes without generating incremental detriment 
to patients’ QOL must be a priority in the advancement of SCCHN therapy. In response to this, 
PROs have been integrated into this study at measurement intervals that represent the appropriate 
balance between allowing a comprehensive HRQOL assessment across all dimensions in the 
proposed questionnaires that are broadly relevant to cancer patients as well as questions that are 
specifically relevant to SCCHN patients as well as a focused assessment of key symptoms from 
these measures, while remaining cognizant of the burden created for the targeted patient population 
by administering these questionnaires. 
4.2.1 
Participant Input into Design  
Patient interviews were conducted to understand potential barriers to participation and general 
reactions to the clinical study design for TrilynX (refer to Study MS202359_0006). Key learnings 
from these interviews were carried over to this study design including the recognition of the 
importance of providing nutritional monitoring and support. Of note, the 60-month follow-up 
requirement was not seen as burdensome and is consistent with what the patients would expect. 
Additional feedback was obtained from a Patient Advocacy meeting which included patient 
advocates, who themselves are patients with LA SCCHN, as well as from care givers of patients 
with LA SCCHN from Europe and the US. Feedback applicable to the current study included the 
following: patients considered the feeding tubes, which are standard supportive care during 
radiation, as challenging and added burden on them as they feel physically and emotionally 
exhausted, but also highlighted that a feeding tube is preferable for food and medication when 
swallowing is painful. In addition, some patients acknowledged that they felt uncared for after 
treatment ended. Therefore, regular follow-up, as implemented in this study, is a way to support 
these patients. 
4.3 
Justification for Dose  
Xevinapant 
Rationale for 200 mg once daily dose: 
Integration of nonclinical pharmacology, clinical efficacy and safety profiles, clinical PK/PD, 
popPK, and exposure-response analyses for efficacy and safety support the recommended 
Phase III dose (RP3D) selection of xevinapant 200 mg/day administered on Days 1 to 14 of a 
3-week cycle with concomitant IMRT, allowing for successive dose reductions to 150 mg and 
100 mg for management of toxicities. 
Specifically: 
• In a Phase II study in participants with high-risk LA SCCHN (Study Debio 1143-201), 
xevinapant showed significant improvement in LRC at 18 months (LRC18; primary endpoint), 
OS, and PFS at a dose of 200 mg/day given on Days 1 to 14 of a 3-week cycle in combination 
with CRT versus CRT alone. Xevinapant chemo-radiosensitizing effects on TEAEs, usually 
associated with RT, were considered manageable and reversible. In the dose escalation part of 
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Study Debio 1143-201, 
. 
• 
 
 
 
 
 
 
 
 
• Exposure-response analyses were conducted based on the pooled datasets of dose escalation 
and randomized parts of Study Debio 1143-201 (n=62 treated with xevinapant). Logistic 
regressions showed that probabilities of LRC18, overall response, complete response, and the 
composite safety endpoint of “mucositis, dysphagia” increased with increasing exposure 
(p<0.05). While statistically significant exposure-response relationships were not discernible 
for all other evaluated safety endpoints or for time-to-event efficacy end points (PFS, OS, or 
duration of LRC), the participants in higher exposure subgroups showed a longer duration of 
LRC. 
• Based on available data, the xevinapant exposure range in this study is expected to be consistent 
with that in Study Debio 1143-201. Currently available urine PK data indicated that about 8 to 
11% of xevinapant is recovered unchanged in urine and suggest a low risk for moderate renal 
impairment to impact PK. Close monitoring of participants with moderate renal impairment 
will be performed. An external DMC will review available PK exposure and safety data in 
participants with moderate renal impairment. Assessment of moderate renal impairment as an 
intrinsic factor on PK via population PK approach is planned once the data in these participants 
become available. 
• Based on the expected MoA of xevinapant in combination with IMRT, conclusions from 
PK/PD, exposure-response and dose-response analyses of xevinapant efficacy in combination 
with CRT are expected to be translatable to a xevinapant / IMRT combination, including 
association between exposure and efficacy endpoints. However, it is noted that the 
comorbidities that make participants ineligible to receive high-dose cisplatin could also make 
them more vulnerable to AEs associated with xevinapant / IMRT administration compared to 
participants eligible to receive cisplatin, as in Study Debio 1143-201. 
 
 
 
 
 
 
Thus, based on the MoA of xevinapant, the patient population in this study, and all available data 
to date, the dosing strategy employed for xevinapant / CRT combination in participants with LA 
SCCHN is also deemed applicable for evaluation of the safety and efficacy of xevinapant in 
combination with IMRT in participants with resected SCCHN, who are at high risk for relapse and 
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are ineligible to receive high-dose cisplatin: i.e. 200 mg/day administered on Days 1 to 14 of a 3-
week cycle. 
Safety monitoring and risk mitigation measures are in place, including individual stepwise dose 
reductions to 150 and 100 mg (Section 6.5.1). 
Rationale for the 7-day off-drug window 
The 7-day off-drug window between 2 cycles (Day 1 to 14 of a 3-week cycle) was implemented 
to reduce the risk for adverse reactions and cumulative toxicity. Xevinapant dosing schedule in all 
clinical studies included an off-drug window, with the D1 to 14 of a 3-week cycle schedule having 
one of the highest dosing intensities among schedules studied (refer to the IB). Other 
investigational IAP antagonists in the clinics, such as CUCDC-427 and ASTX660, use intermittent 
dosing regimens in clinical studies (Mita 2020, Tolcher 2016). Of note, one participant death due 
to liver failure was reported in a Phase I study with the investigational IAP antagonist CUDC-427 
using a monotherapy continuous twice daily administration schedule (Curis 2014), which triggered 
a partial clinical hold by US FDA. The amended Phase I study of CUDC-427 with daily 14 day 
on/7 day off regimen showed an acceptable safety profile in participants with refractory solid 
tumors (Tolcher 2016). 
Based on MoA with RT, i.e sensitization of RT-induced cell death, intermittent dosing with partial 
target coverage in the off-drug window is unlikely to compromise efficacy. To this end, xevinapant 
showed efficacy in both SCCHN mouse models and in participant with LA SCCHN in Study Debio 
1143-201 using an intermittent dosing regimen. Furthermore, nonclincial studies with ASTX660 
in breast cancer models, suggested that regimens with continuous and intermittent dosing have 
similar efficacy and an improved therapeutic window (Ward 2018). 
Population PK/PD modeling based on Phase I data suggested that partial IAP inhibition by 
xevinapant is maintained during the 7-day off-drug window with the 200 mg/day dose 
administered on Days 1 to 14 of a 3-week cycle, similar to clinical PK/PD data reported for 
ASTX660 and CUDC-427 (Tolcher 2016, Mita 2020). Thus, the intermittent dosing regimen 
selected for xevinapant may allow for maintained sensitization of RT-induced cell death during 
the 7 day off-drug windows, while reducing the potential of adverse reactions. 
 
 
 
 
 
 
 
 
 
 
 
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IMRT 
High-dose RT (60 to 72 Gy) is necessary to potentially cure high-risk resected LA SCCHN 
patients. Irradiation of critical normal tissue can cause severe side effects with increased acute and 
late morbidity (Marta 2017). Newer techniques have been developed over the past 2 decades to 
improve delivery of RT with 2 aims. Firstly, to avoid critical dose to normal tissue to decrease 
toxicity (Jellema 2007). Secondly, to administer a dose to the tumor volume high enough in order 
not to compromise control rates (Ghosh-Laskar 2016). 
According to the NCCN/ESMO guidelines, IMRT is now considered the SoC for treating SCCHN 
both in curative and in postoperative locally advanced setting. In the postoperative setting, the 
recommended radiation dose is 66 Gy over 33 fractions (NCCN v3 2021, Machiels 2020). The 
dose should follow the ICRU recommendations and using IMRT with boost SIB technique. 
4.4 
End of Study Definition  
The primary completion date is defined as the data cut-off date for the primary DFS analysis when 
the planned number of events has been reported. After the primary completion date, follow-up 
continues until the final analysis (Section 9.4) in case the study has reached its primary objective. 
The end of the study is defined as the date of the last visit of the last remaining on-study participant. 
All remaining participants will be taken off study once a decision to end the study has been 
triggered or after 60 months of FU after randomization of the most recently recruited participant 
who is still on study, whatever occurs earlier. At this timepoint, all participants who have not 
previously discontinued from the study prematurely will undergo the EOS assessments as specified 
in Section 1.3 and will be considered as having completed the study. 
A participant has completed the study if he/she has completed all study parts, including the last 
visit or the last schedule procedure shown in Section 1.3. Participants will be receiving the 
appropriate follow-up treatment per institutional standards. 
5 
Study Population  
The study will enroll resected LA SCCHN participants who are at high risk of relapse and are not 
eligible for cisplatin-based chemoradiotherapy postoperatively. 
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The criteria in Sections 5.1 and 5.2 are designed to enroll only participants who are appropriate for 
the study; thereby, ensuring the study fulfills its objectives. All relevant medical and nonmedical 
conditions are considered when deciding whether a participant is suitable for this study. 
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Before performing any study assessments that are not part of the participant’s routine medical care, 
the Investigator will confirm that the participant or the participant’s legal representative (where 
allowed by local laws and regulations) has provided written informed consent, as indicated in 
Appendix 6. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the following criteria apply: 
Category 
Criterion 
Age 
1. Are ≥ 18 years of age (or based on the country legal age limit for 
adults if >18 years) at the time of signing the informed consent. 
Type of Participant 
and Disease 
Characteristics 
2. Have ECOG PS 0-2 and able to tolerate standard of care IMRT 
treatment according to Investigator assessment. 
3. Have histologically confirmed squamous cell carcinoma with one 
of the following primary sites: oral cavity, oropharynx, 
hypopharynx or larynx. Participants have received surgery with 
curative intent on these sites in the past 4 to 10 weeks before start 
of treatment (C1D1) (Note: Participants with 2 or more primary 
SCCHN tumors are not eligible for this study).  
4. Participants with HPV-negative oropharynx cancers as determined 
by testing p16 expression using immunohistochemistry (IHC), with 
oral cavity, hypopharynx or larynx cancers with the following 
pathological staging (pTNM stage according to the American Joint 
Committee on Cancer AJCC/TNM Staging System 8th Edition): 
• pIII or 
• pIVA or pIVB 
• OR 
Participants with HPV-positive oropharynx cancers, as determined 
by testing p16 expression using IHC, must be smokers > 25 Pack-
Year, and must have the following pTNM stage (according to the 
AJCC/TNM Staging System 8th Edition): 
• pT3 and pN2 or 
• pT4 and pN2 
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Category 
Criterion 
OPC participants must have known HPV status as determined by p16 
expression using IHC (pathological report should be available). For 
OPC participants, a positive p16 expression score is defined in 
Section 8.2.4.1. Note: If the site is not able to perform HPV testing by 
p16 IHC, it will be evaluated by a central laboratory. 
5. Archival/preradiotherapy FFPE tumor tissue samples from 
participant must be provided, if local regulations allow. If an 
archival FFPE tissue block cannot be provided, at least 15 unstained 
FFPE tissue slides will be acceptable. 
6. Have no residual disease by CT/MRI and have a high risk of relapse 
with 1 or 2 of the following criteria, confirmed by local 
histopathology: 
• nodal extra-capsular extension (ECE) 
• positive resection margins (R1 or close margin ≤ 1 mm). 
7. Have a postoperative general condition which allows to perform 
postoperative radiotherapy. 
8. Are able to swallow liquids or have an adequately functioning 
feeding tube, gastrostomy, or jejunostomy placed. For participants 
requiring liquid nutrition at baseline or during the study including 
the follow-up period, access to liquid nutrition supply should be 
ensured. 
9. Are unfit to receive high-dose cisplatin by meeting one or more of 
the following criteria: 
• eGFR < 60 mL/min /1.73 m2 (using the CKD-EPI creatinine 
formula). See Appendix 12 for specific requirements in Japan 
for CKD-EPI creatinine formula.  
• History of hearing impairment, defined as Grade ≥ 2 
audiometric hearing loss or tinnitus Grade ≥ 2. An audiogram is 
not required if one of the other criteria meets unfitness to receive 
high-dose cisplatin. See Appendix 12 for specific requirements 
in France and the US. 
• Peripheral neuropathy ≥ Grade 2 
• If ≥ 70 years, unfit according to G8 questionnaire (Score ≤ 14) 
or ineligible for cisplatin treatment due to age limit according to 
national guidelines. 
10. Have adequate renal, hematologic and hepatic function as indicated 
by: 
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Category 
Criterion 
• eGFR ≥ 30 mL/min/1.73m² (using the CKD-EPI creatinine 
formula). See Appendix 12 for specific requirements in Japan 
for CKD-EPI creatinine formula. 
• Absolute neutrophil count ≥ 1,000 cells/μL 
• Platelets ≥ 75,000 cells/μL 
• Hemoglobin ≥ 9.0 g/dL (blood transfusions during Screening 
are permitted) 
• AST and ALT ≤ 2.5 × 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) 
Sex and 
Contraception/Barrier 
Requirements 
11. All sexes allowed 
Contraceptive use will be consistent with local regulations on 
contraception methods for those participating in clinical studies. 
The Investigator confirms that each participant agrees to use 
appropriate 
contraception 
and 
barriers, 
if 
applicable. 
The 
contraception, barrier, and pregnancy testing requirements are below. 
Please see Appendix 12 for duration of contraception requirements in 
South Korea. 
a. A female participant 
• Is not breastfeeding 
• Is not pregnant (i.e. has a negative serum pregnancy test, as 
required by local regulations, within 24 hours before the first 
dose of study intervention) 
• Is not a WOCBP 
o If a WOCBP, uses a highly effective contraceptive 
method (i.e. with a failure rate of < 1% per year), 
preferably with low user dependency, as described in 
Appendix 4 for the following time periods: 
1. Before the first dose of the study intervention(s), if 
using hormonal contraception: 
o Has completed at least one 4-week cycle of an oral 
contraception pill and either had or has begun her 
menses; OR, 
o Has used a depot contraceptive or extended-cycle 
oral contraceptive for least 28 days and has a 
documented negative pregnancy test using a 
highly sensitive assay. 
2. During the study intervention period 
3. After the study intervention period (i.e. after the last 
dose of study intervention is administered) for at 
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Category 
Criterion 
least 3 months, after the last dose of study 
intervention and agree not to donate eggs (ova, 
oocytes) for reproduction during this period. 
4. Female participants using hormonal contraception 
must also use a barrier contraception method 
(preferably male condom) due to potential risk of 
CYP3A4/5 induction by xevinapant which may 
reduce hormonal contraception efficacy. 
 
The Investigator evaluates the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention. 
The Investigator reviews the medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a female with 
an early undetected pregnancy. 
b. A male participant 
Agrees to the following during the study intervention period 
and for at least 3 months after the last dose of study 
intervention: 
•  Refrains from donating fresh unwashed semen 
PLUS, either 
o Abstains from any activity that allows for exposure to 
ejaculate 
OR 
Uses a male condom: 
o When having sexual intercourse with a WOCBP, who 
is not currently pregnant, and instructs her to use a 
highly effective contraceptive method with a failure 
rate of < 1% per year, as described in Appendix 4 
since a condom may break or leak. 
o When engaging in any activity that allows for 
exposure to ejaculate. 
Informed consent 
12. Are capable of giving signed informed consent, as indicated in 
Appendix 6, which includes compliance with the requirements and 
restrictions listed in the ICF and this protocol. 
ALT=alanine transaminase, AST=aspartate aminotransferase, CKD-EPI=Chronic Kidney Disease Epidemiology 
Collaboration, CT=computed tomography, ECOG PS=Eastern Cooperative Oncology Group Performance Status, 
eGFR=estimated glomerular filtration rate, FPPE=formalin-fixed paraffin-embedded, HPV=human papillomavirus, 
IHC=immunohistochemistry, ICF=informed consent form, IMRT=Intensity modulated radiation therapy, 
OPC=oropharynx, SCCHN=squamous cell carcinoma of the head and neck, ULN=upper limit of normal. 
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5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Category 
Criterion 
Medical Conditions 
1. Any condition, including any uncontrolled disease state other than 
SCCHN that in the Investigator’s opinion constitutes an 
inappropriate risk or a contraindication for participation in the study 
or that could interfere with the study objectives, conduct, or 
evaluation. 
 
2. Primary tumor of nasopharyngeal, paranasal sinuses, nasal cavity, 
salivary, thyroid or parathyroid gland, skin or unknown primary site. 
 
3. Participant with incomplete surgery i.e. R2 resection (AJCC/TNM 
Staging System 8th Edition) 
 
4. Recurrent or metastatic disease (Stage IVC as per AJCC/TNM 
Staging System 8th Edition). 
 
5. Known history of infection with HIV. If unknown history of HIV, 
an HIV screening test must be performed, where allowed by local 
regulations, and participants with positive serology for HIV-1/2 
must be excluded. 
 
6.  Chronically active HBV or HCV infection. The following tests 
must be performed at the central lab and participants with positive 
serology must be excluded (Section 8.2.4): 
• HBV screening tests: both HBsAg and HBcAb  
(see Appendix 12 for specific requirements in Japan) 
• HCV screening tests: both HCV-antibody and positive viral load 
HCV-RNA by PCR 
 
7. Other infections (viral [including COVID-19] and/or bacterial 
and/or mycotic) requiring systemic treatment, including a 
SARS-CoV-2 positive test during the screening period, either 
symptomatic or asymptomatic, PCR or antigen test proven. 
Note: No test will be required for participants who have completed 
prophylactic vaccination as per local regulations against 
SARS-CoV-2 or who have recovered from confirmed COVID-19 
within the screening period, as per local regulations. 
 
8. Known gastrointestinal disorder with clinically established 
malabsorption syndrome and major gastrointestinal surgery in the 
last 12 months that may limit oral absorption. 
 
9. Documented weight loss of > 10% during the last 4 weeks prior to 
surgery (unless adequate measures are undertaken for nutritional 
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Category 
Criterion 
support), OR plasmatic albumin < 3.0 g/dL. No albumin 
transfusions are allowed within 2 weeks before randomization. 
 
10. 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. 
 
11. Active inflammatory disease (including rheumatoid arthritis, 
systemic lupus erythematosus, Sjögren syndrome, severe extensive 
psoriasis, inflammatory bowel diseases, pneumonitis, and other 
autoimmune diseases) requiring ongoing treatment with anti-TNF 
medication. 
 
12. Impaired 
cardiovascular 
function, 
clinically 
significant 
cardiovascular diseases, or clinically significant pulmonary 
disease, 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, uncontrolled 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 > 470 ms. 
• Symptomatic pulmonary disease requiring continuous or 
intermittent oxygen supply. 
• Hypertension uncontrolled by medication (i.e. systolic blood 
pressure ≥ 160 mmHg and diastolic blood pressure 
≥ 100 mmHg). 
 
13. History of another malignancy prior to randomization, with the 
following exceptions:  
• Completely resected nonmelanoma cell skin cancer outside the 
head and neck area or completely resected stage I breast cancer, 
or completely resected in-situ nonmuscular invasive bladder, 
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Category 
Criterion 
cervix and/or uterine carcinomas, or T1a squamous esophageal 
carcinomas.  
• Prior malignancy treated with curative intent and no relapse and 
no anti-cancer treatment within the last 3 years and does not 
have potential to interfere with the safety or efficacy 
assessments of the study. 
 
14. Noncompensated or symptomatic liver cirrhosis (Child-Pugh 
score: B or C). 
Prior/Concomitant 
Therapy 
15. Prior definitive, neoadjuvant, concurrent or adjuvant (C)RT to the 
head and neck region which may jeopardize the primary tumor 
irradiation plan, or any other prior SCCHN systemic treatment, 
including investigational agents.  
 
16. 
Use of the following: 
• Prohibited medication. These medications and time window 
to stop these medications prior to randomization are further 
specified in Section 6.8.3 
• Treatment with an investigational agent or use of an 
investigational device within 4 weeks of the first dose of study 
treatment or during study treatment 
• Live attenuated vaccines within 28 days prior to first study 
intervention administration 
• Concurrent use of anticancer therapy.  
 
17. Patients with active immunodeficiency or patients receiving 
ongoing immunosuppressive therapy. 
 
18. 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. 
 
19. Major surgical intervention outside the head and neck area within 
4 weeks prior to the first dose of study intervention. Biopsies to 
establish the diagnosis for SCCHN are permitted.  
 
20. Prior organ transplantation, including allogeneic stem cell 
transplantation. 
Prior/Concurrent 
Clinical Study 
Experience 
21. Participation in any interventional clinical study within 28 days 
prior to screening or during participation in this study. 
Diagnostic 
Assessments 
22. Known contraindication to undergoing positron emission 
tomography with 18F-FDG-PET-CT scans, or both contrast-
enhanced MRI and contrast-enhanced CT scans.  
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Category 
Criterion 
Other Exclusions 
23. Known allergy to xevinapant or any excipient known to be present 
in xevinapant or in the placebo formulation. 
 
24. Pregnant or nursing (lactating) women. 
 
25. Any social, personal, medical and/or psychologic factor(s), 
including current alcohol and/or drug abuse that could interfere in 
the opinion of the Investigator with the observance of the 
participant to the protocol and/or the follow-up and/or the signature 
of the informed consent. 
(C)RT=(chemo)radiotherapy, HBV=hepatitis B virus, HBcAb=hepatitis B core antigen; HBsAG = hepatitis B surface 
antigen; HCV=hepatitis C virus, HIV=human immunodeficiency virus, 18F-FDG-PET=2-deoxy-2- [fluorine-18] fluoro-D-
glucose positron emission tomography, PCR=polymerase chain reaction; MRI=magnetic resonance imaging, QTcF= 
QTc using Fridericia’s formula; SARS-CoV-2=Severe acute respiratory syndrome coronavirus-2; SCCHN=squamous 
cell carcinoma of the head and neck. 
5.3 
Lifestyle Considerations  
5.3.1 
Meals and Dietary Restrictions  
Abstain from consumption of the following from 1 day before the start of study intervention until 
after the final dose: Seville oranges, grapefruit or grapefruit juice, or 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 (Section 6.8.3). 
Xevinapant / placebo should be administered orally, in the morning (see exceptions and further 
instructions in Section 6.5.1). 
5.4 
Screen Failures  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened if the condition leading to screen failure has resolved and after discussion with the 
Medical Monitor. Rescreened participants will be assigned a new participant number. Only one 
rescreening is allowed. 
Re-testing of participant in cases of physical and/or laboratory parameter 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 rescreened in certain circumstances for enrollment 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). 
• 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. 
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In case of rescreening, the participant will be required to sign another ICF. A new eCRF will be 
used. All assessments should be repeated according to instructions provided for the initial 
screening (see Section 1.3 and Table 1). As with initial screening procedures, IV 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, if required, HIV 
test, and fiberoptic endoscopy, if appropriate, performed within 2 weeks before the last signed ICF 
do not have to be repeated during screening. 
5.5 
Criteria for Temporarily Delaying the Randomization/ 
Administration of Study Intervention Administration  
Not applicable. 
6 
Study Intervention(s) and Concomitant Therapies  
Study intervention is any investigational intervention(s), marketed product(s), placebo, or medical 
device(s) intended to be administered to a study participant per the study protocol. 
6.1 
Study Intervention(s) Administration  
See Section 4.1 for the allocation to each arm. 
 
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Arm Name 
A: Xevinapant + IMRT 
B: Placebo + IMRT 
Arm Type 
Experimental 
Placebo comparator 
Arm Description 
3 cycles of xevinapant + IMRT followed by 3 cycles of xevinapant 
3 cycles of placebo + IMRT followed by 3 cycles of placebo 
Intervention Name 
Xevinapant 
IMRT 
Placebo 
IMRT 
Type  
Drug 
Radiation 
Placebo 
Radiation 
Dose Formulation 
Oral solution 
NA 
Oral solution 
NA 
Unit Dose Strength 
 of 10 mL containing 
200 mg xevinapant (20 mg/mL) 
NA 
 of 10 mL containing 
placebo 
NA 
Dose Amount 
200 mg 
66 Gy 
NA 
66 Gy 
Frequency 
Once daily  
Day 1-14 of a 3-week cycle 
2 Gy once daily 5 days/week 
for a total of 33 fractions 
Once daily  
Day 1-14 of a 3-week cycle 
2 Gy once daily 5 days/week 
for a total of 33 fractions 
Route of 
Administration 
Oral 
NA 
Oral 
NA 
Use 
Experimental 
Background intervention 
Placebo to xevinapant 
Background intervention 
IMP/NIMP 
IMP 
NA 
IMP 
NA 
Sourcing 
Provided centrally by the 
Sponsor 
NA 
Provided centrally by the 
Sponsor 
NA 
Packaging and 
Labeling 
Xevinapant
 
 will be 
packed and labeled per all 
applicable regulatory 
requirements and GMP 
Guidelines. 
Packaging and labeling will be 
prepared to protect the blinded 
nature of the study. 
NA 
Matched placebo 
 
 
will be packed and labeled per 
all applicable regulatory 
requirements and GMP 
Guidelines. 
Packaging and labeling will be 
prepared to protect the blinded 
nature of the study. 
NA 
Former Name  
Debio 1143 
NA 
NA 
NA 
IMP=investigational medicinal product, IMRT=intensity modulated radiation therapy, NA=not applicable, NIMP=noninvestigational medicinal product. 
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6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability  
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study intervention accountability, reconciliation, and record maintenance (i.e. receipt, 
reconciliation, and final disposition records). 
• Upon receipt of the study intervention(s), the Investigator or designee will confirm appropriate 
temperature conditions have been maintained during transit and any discrepancies are reported 
and resolved before use. Also, the responsible person will check for accurate delivery. Further 
guidance and information for study intervention accountability are provided in the Pharmacy 
Manual. 
• Only participants enrolled in the study may receive study intervention(s) and only authorized 
site staff may supply it. All study intervention(s) will be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area, per the labeled storage conditions, and 
with access limited to the Investigator and authorized site staff. 
• Dispensing will be recorded on the appropriate accountability forms so that accurate records 
will be available for verification at each monitoring visit. 
• Study intervention(s) accountability records at the study site will include the following: 
o Confirmation of receipt, in good condition and in the defined temperature range. 
o The inventory provided for the clinical study and prepared at the site. 
o The dose(s) each participant used during the study. 
o The disposition (including return, if applicable) of any unused study intervention(s). 
o Dates, quantities, batch numbers, kit numbers, expiry dates, and the participant numbers. 
• The Investigator site will maintain records, which adequately documents that participants were 
provided the doses specified in this protocol, and all study intervention(s) provided were fully 
reconciled. 
• Unused study intervention(s) will not be discarded or used for any purpose other than the 
present study. No study intervention that is dispensed to a participant may be re-dispensed to a 
different participant. 
• A Study Monitor will periodically collect the study intervention(s) accountability forms. 
• Further guidance and information for the final disposition of unused study intervention(s) are 
provided in the Pharmacy Manual. 
• Additional instructions for the preparation, handling, storage, and disposal of 
xevinapant/placebo will be provided in the Pharmacy Manual. 
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6.3 
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding  
6.3.1 
Study Intervention Assignment  
After confirmation of participant’s eligibility and at the last practical moment prior to study 
intervention administration, participants will be centrally allocated to either Arm A or Arm B in a 
1:1 ratio using an IWRS and per a computer-generated randomization list. 
 
 
 
 
 
The IWRS will be used to assign unique participant numbers, allocate participants to study 
intervention group at the randomization visit, and study intervention to participants at each study 
intervention visit. 
Before the study is initiated, the directions for the IWRS will be provided to each site. 
6.3.2 
Blinding  
Blinding Method 
The study will be double-blind. At randomization and treatment allocation, a blinded treatment kit 
number will be allocated by the IWRS to each participant corresponding to their randomization 
group. Experimental treatment kits will be indistinguishable from the placebo. 
Randomization codes will be kept strictly confidential, accessible only to authorized staff (i.e. 
randomization statistician, unblinded statistician), until the time of unblinding. All other study-
related individuals, ancillary site staff, clinical research associates/monitors, the Investigator, IRC, 
participants, Sponsor (excluding Clinical Trial Supply), and clinical research organization staff 
will remain blinded to study intervention until after the primary analysis (Section 9.4.4). 
Interim analyses before unblinding will be conducted by an external study independent unblinded 
statistician, programmer, and clinical pharmacologist, who get access to the actual treatment codes 
only after database is locked to conduct the analyses and provide the external DMC with 
corresponding results. The external DMC may request unblinded analyses, which are usually 
masked (i.e. presented by study intervention arm, but actual study intervention is not revealed) for 
the periodic safety reviews. 
Confirmation of the Indistinguishability of the Study Interventions 
Xevinapant and matching placebo 
 are identical in color and appearance. 
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Unblinding for Sample Analysis of Special Data 
The analytical laboratories responsible for analyses of PK will be unblinded to study treatment 
codes to enable testing of xevinapant plasma concentration (and metabolite D-1143-MET1) prior 
to database lock. 
Xevinapant and metabolite D-1143-MET1 plasma concentration information that may unblind the 
study participants will not be reported with participant identifiers to investigative sites or blinded 
personnel until the study has been unblinded. 
6.3.3 
Emergency Unblinding  
In an emergency, the Investigator is solely responsible for determining if unblinding of a 
participant’s study intervention assignment is warranted. Participant safety is always the first 
consideration in this decision. 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. If the 
Investigator decides that unblinding is warranted, the Investigator makes every effort to contact 
the Sponsor prior to the unblinding, unless this could delay emergency treatment. The Sponsor 
will be notified within 24 hours after unblinding. The Investigator will provide the Sponsor the 
reason for unblinding without revealing the study intervention, except to the designated global 
patient safety representative via the Emergency Unblinding Notification Form. The date of and 
reason for unblinding will be recorded in the source documents and eCRF. Contact information 
for unblinding in an emergency is given on the participant emergency card provided to each 
participant, as noted in Appendix 6. If emergency unblinding is required, the participant can 
continue study treatment unless there are other circumstances that require participant 
discontinuation. 
The Sponsor’s global patient safety department will submit any SUSAR reports to regulatory 
authorities and ethics committees with unblinded information, per applicable regulations. Only 
blinded information will be provided to the study team. 
6.4 
Study Intervention Compliance  
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents and recorded in the eCRF. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention. Study 
site personnel will examine each participant’s mouth to ensure that the study intervention was 
ingested. 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by monitoring the Patient 
Diary filled out by the participant after each intake (Section 8.2.6) during the site visits and 
documented in the source documents and eCRF. Any deviation(s) from the prescribed dosage 
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regimen are recorded in the eCRF. Participants will be instructed to return used and unused 
xevinapant or placebo
 to the site to allow drug accountability by the medical staff. 
A record of the number of xevinapant / placebo 
dispensed to and taken by each participant 
will be maintained and reconciled with study intervention and compliance records. Intervention 
start and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded in the eCRF. In addition, for each study intervention (xevinapant/ placebo, and IMRT) 
the reasons for dose modification, interruption, and discontinuation must be recorded in the CRF. 
6.5 
Dose Modification  
6.5.1 
Xevinapant or Placebo Dosing and Administration  
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 (Figure 1 and Table 3). Xevinapant / placebo 
should be administered orally, in the morning (except for days of PK sampling when the dose is 
taken at the hospital where a specific procedure applies as described below [see also Table 6]). If 
necessary,
 will be administered 
 
 
If the participant forgets to take the dose of xevinapant / placebo more than 8 hours after the 
scheduled time of intake, then the participant should skip that dose. 
Xevinapant / placebo will be dispensed by the medical staff or pharmacist of the investigational 
sites. The participant will receive xevinapant or the placebo on an outpatient basis. 
On the days of C1D1, C1D2, C1D8, C2D2, C2D8, C4D1, C5D1, and C6D1 participants must be 
at the clinical unit before xevinapant / placebo is administered to ensure PK blood sample 
collection as per SoA (Table 6). The time of dosing on those days and time of the draw must be 
recorded in eCRF. 
On C3D8, xevinapant / placebo dose is encouraged to be taken at home and the time of the last 
dose prior to PK sample is recorded by participant in the diary and reported in the eCRF. 
The treatment schedule of xevinapant / placebo is presented in Table 1, Table 2, and Table 3. 
Participants will be instructed by the medical staff on how to self-administer xevinapant / placebo 
at home. The participant should inform the medical staff of any missed or delayed doses. In 
addition, a Patient Diary will be provided to participants to record xevinapant / placebo intakes at 
home (Section 6.4 and Section 8.2.6). 
6.5.1.1 
Concurrent Administration to IMRT  
On days when IMRT is to be administered (Table 3 and Section 6.5.2), xevinapant or placebo 
should be administered in the morning, before IMRT. 
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If IMRT is put on hold or discontinued due to toxicity, adapt xevinapant / placebo administration 
as described in Section 6.5.1.2. Otherwise xevinapant / placebo treatment should continue as per 
protocol. 
6.5.1.2 
Dose Modification, Interruption and Discontinuation of 
Xevinapant / Placebo Treatment  
For participants who do not tolerate the study interventions, adjustments to the study interventions 
are permitted to allow the participant to continue on-study treatment. 
The guidelines for xevinapant / placebo dose modifications for toxicities considered at least 
possibly related to study intervention for combination therapy and monotherapy are outlined 
Table 8. These dose modifications are recommendations unless otherwise specified as mandatory. 
All dose modifications should be based on the worst preceding toxicity (NCI-CTCAE v5.0). 
Additionally, nontreatment-related events or unexpected toxicities may require interruption of 
study intervention at the discretion of the Investigator. 
The volume of the oral solution equivalent to each dose level is the following: 
Planned dose (Level 0) 
mL/day, corresponds to 200 mg/day of xevinapant 
Dose Level -1 
mL/day, corresponds to 
 mg/day of xevinapant 
Dose Level -2 
 mL/day, corresponds to 
mg/day of xevinapant 
In case a dose reduction is necessary, the study intervention will be administered as follows: 
For each participant, a maximum of 2 dose level reductions of xevinapant / placebo will be allowed 
during the study. These dose reductions only apply to a starting dose of 200 mg/day of xevinapant. 
General rules for xevinapant / placebo administration throughout the treatment period (C1 to C6) 
are: 
The number of treatment days with xevinapant intake should not exceed 14 days per cycle. 
• In case of tolerability issues, up to 2 sequential xevinapant dose reductions of 
 
 per step will be allowed, down to a minimum dose of 
 
. If further dose reduction is required, the participant must be 
permanently discontinued from xevinapant / placebo administration (IMRT can continue, see 
Sections 6.5.2.3). 
• If the onset of several toxicities leads to conflicting recommendations (as described in 
Table 8), the most conservative dose adjustment among all toxicities presented must be 
followed. 
• No re-escalation of xevinapant / placebo dose after dose reduction will be allowed during 
the study. Once xevinapant / placebo dose has been reduced, participants will keep receiving 
the same dose until the EOT, or until further dose reduction or permanent treatment 
discontinuation, if required due to tolerability issues. 
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• Xevinapant / placebo doses 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. 
• Combination treatment period: If IMRT is interrupted due to toxicity, xevinapant / placebo 
should be interrupted. If IMRT is restarted, xevinapant / placebo should be resumed at the next 
originally scheduled intake day of xevinapant / placebo, provided other rules of dose 
interruption are not met (Section 6.5.2). If IMRT is permanently discontinued due to safety 
issues, then xevinapant / placebo administration should be maintained. 
• Monotherapy treatment period: If a participant requires a xevinapant / placebo dose interruption 
of more than 21 consecutive days due to study intervention-related toxicities, the Investigator 
should consider discontinuing the study intervention. If a participant is discontinued from the 
monotherapy treatment, the EOT visit must be performed. Hereafter, the participant will 
continue with the study as per schedule and will enter the DFS FU period. 
• Xevinapant / placebo interruption or discontinuation during the combination treatment period, 
will NOT result in IMRT discontinuation. 
• Participants who prematurely discontinue from all treatments, i.e. xevinapant / placebo, and 
IMRT in the absence of an DFS event, will undergo the EOT visit and then enter the DFS 
follow-up period according to schedule. 
• Any dose modification and dose interruption including the reason must be collected on the drug 
administration form in the eCRF.
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6.5.1.3 
End of Xevinapant / Placebo Treatment  
Xevinapant / 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 will enter the monotherapy period. Discontinuation 
from study intervention does not mean discontinuation from the study. Procedures to be followed 
in the event of a study intervention discontinuation are described in Section 7.1. Procedures for 
discontinuation from study (not only study intervention) are described in Section 7.2. 
6.5.2 
Radiotherapy  
6.5.2.1 
General Considerations  
The general recommendation is to start IMRT as soon as a diagnosis and management decision 
has been decided. 
The following guidelines must be applied: 
• Nutritional support: Maintaining adequate nutritional is essential during the course of 
radiotherapy (Section 6.8.4.1). 
• Dental care: Before the participants start IMRT, dental assessment is mandatory, and 
appropriate dental care should be provided (Section 6.8.4.2). 
Refer to the RT Manual for further guidance. 
6.5.2.2 
Treatment  
Full details of radiotherapy protocol requirements, including volumes, OAR, and OAR dose 
constraints can be found in the RT Manual provided for this study. A QA procedure will be applied 
for this study. The RT-QA Review Center (Appendix 6) will centrally review the IMRT treatment 
plan(s) including other treatment-related information submitted by the Investigator to ensure 
compliance with protocol guidelines and provide feedback to the site (refer to the RT-QA Manual). 
The IMRT plan must be approved by the RT-QA Review Center prior to the start of the IMRT. A 
summary of radiotherapy requirements and recommendations is described below. 
Initiation of radiotherapy must start 4 to 10 weeks after surgery on C1D1 of xevinapant / placebo. 
If possible, it is recommended to start treatment within 8 weeks from surgery. 
 
 
 A matched 
conventional anterior neck field is not permitted. During treatment, daily image guided radiation 
therapy (IGRT) is required with either kV or MV guidance. 
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For CT simulation, the participant must be in a supine position and immobilized with a 
thermoplastic (or similar) mask that includes the head and neck with strong consideration of the 
shoulders as well. Intraoral immobilization devices are at the discretion of the Investigator. A slice 
thickness of 3 mm or less is required and the field of view must extend from the top of skull to the 
bottom of the carina. Intravenous contrast is recommended at the time of simulation, and if not 
possible, co-registration of a postoperative diagnostic CT of the neck with IV contrast is strongly 
recommended. Co-registration with pre-operative imaging (e.g. CT, PET, MRI) is encouraged to 
assist with treatment planning, but with caution given anatomical changes related to surgery. 
Target volumes must consider all clinical, endoscopic, and imaging information along with 
surgical and pathologic findings. Since eligible participants must have gross total resections, there 
will be no GTV. 
Clinical target volumes (CTV) will be divided into 2 regions: high risk and low risk; these will be 
treated at different dose levels using a SIB technique delivered over 33 fractions (Table 9). 
Table 9 
Dose Prescription  
Clinical Target Volume Region 
Total Dose 
Dose per Fraction 
Target 
Very High Risk 
66 Gy 
2 Gy 
Regions with positive / close 
margins and/or extra-capsular 
extension 
Low Risk 
54.45 Gy 
1.65 Gy 
Regions at risk for 
microscopic / subclinical 
disease 
The delineation of the elective nodal CTV for participants with positive neck nodes can be based 
on the consensus guidelines published by Gregoire (2006). Additional details will be provided in 
the RT Manual. 
Planning Target Volumes (PTV) will be a uniform 3 to 5 mm expansion to all CTVs to account 
for interfraction motion and setup uncertainties. The SIB treatment plan will be prescribed to the 
PTV and coverage requirements are detailed in the Radiotherapy Guidelines. If a PTV is close to 
the spinal cord or other critical normal tissue, a PTVeval can be created and adjusted for treatment 
planning purposes. The requirements for organ at risk definition and dose constraints are listed in 
the RT Manual. 
All participants will have daily pretreatment imaging to ensure appropriate repositioning, the 
details will be described in the RT Manual. 
IMRT (fully described in the RT Manual) is to be started on C1D1 after administration of 
xevinapant / placebo (Table 1 and Table 3). On days where all treatment components should be 
administered, IMRT should be administered after xevinapant / placebo administration. 
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6.5.2.3 
Treatment Interruption  
Interruption of radiotherapy is strongly discouraged and every attempt should be made to keep the 
treatment continuous and adhere to the overall treatment time as prescribed (6.5 weeks). Planned 
radiotherapy interruptions are not allowed. Any interruption must be clearly indicated in the 
treatment record and reasons should be documented. Radiotherapy may be interrupted for a 
maximum of 10 treatment days in total to allow resolution / improvement of chemoradiation 
toxicities such as Grade 4 mucositis or other Grade 3 or 4 in-field treatment-related AEs (for 
example skin side effects) measured by physical or functional examination, or Grade 4 
radiodermatitis (see Section 6.5.2.4 for management of these toxicities). 
Treatment interruption due to nonmedical reasons must be minimized and should not exceed 
2 consecutive treatment days per interruption. In case of technical reasons (e.g. malfunction of the 
treatment machine), continued treatment must be ensured, and the use of another unit is 
recommended. 
If IMRT is interrupted due to toxicity, xevinapant / placebo should be interrupted (Section 6.5.1.2), 
otherwise xevinapant / placebo treatment should continue as per protocol. 
No more than 5 fractions will be administered in a given week, unless one previously skipped 
fraction has to be compensated. If a fraction has to be compensated, it can be administrated at the 
end of the treatment or it can be compensated during treatment. In the latter case, the fractions 
should be at least 6 hours apart. Xevinapant / placebo administration should not be compensated. 
If IMRT is permanently discontinued due to severe and intolerable toxicities as per Investigator’s 
judgment, then xevinapant / placebo administration must be maintained, and the participant can 
enter the monotherapy period (Section 6.5.1.3). 
6.5.2.4 
Management of Acute “Radiation In-Field” Toxicity  
If dermatitis, mucositis, or dysphagia occurs, the possibility of IMRT interruption must 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 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 ≥ 5%. If the weight loss is ≥ 10%, 
the use of a nasogastric or gastrostomy tube must be implemented as quickly as possible 
(Elad 2019) and access to adequate nutritional support needs to be secured by the Investigator. 
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The management of radiation dermatitis must be based on the severity of symptoms, as determined 
by Radiation Therapy Oncology Group and must be aligned with the recommendations by the 
Supportive Care Guidelines Group. 
6.5.2.5 
End of IMRT  
Radiotherapy will be administered until completion of the IMRT dose and schedule planned in the 
study (Table 9) or until any of the study intervention discontinuation criteria described in 
Section 7.1 occur. 
Discontinuation from study intervention does not mean discontinuation from the study. Procedures 
to be followed in the event of a study intervention discontinuation are presented in Section 7.1. 
Procedures for discontinuation from study (not only study intervention) are described in 
Section 7.2. 
6.6 
Continued Access to Study Intervention After the End of the Study  
Not applicable. 
6.7 
Treatment of Overdose  
For this study, any dose of xevinapant greater than 200 mg/day will be considered an overdose. 
The Sponsor has no specific recommendation for treating an overdose. The Investigator will use 
his/her clinical judgment to manage any overdose, considering the symptoms and any site 
procedures or standards. 
Even if not associated with an AE or a SAE, any overdose is recorded in the eCRF and reported 
to global patient safety in an expedited manner. Overdoses are reported on a SAE and Overdose 
Report Form, following the procedure in Appendix 8. 
6.8 
Concomitant Therapy  
Record in the eCRF all concomitant therapies (e.g. medicines or nondrug interventions) used from 
the time the participant signs the informed consent until FU28 visit or until the start of next line 
anticancer therapy, whichever occurs earlier. Record all concomitant therapies used at occurrence 
of late onset AESIs (Section 8.3.7.2) and related SAEs during the period immediately after the 
FU28 visit until completion of the study. Record all new antineoplastic therapies (medication, 
surgery, any further RT) from EOT until completion of the study, including any changes. For 
prescription and over-the-counter medicines, vaccines, vitamins, and herbal supplements, record 
the name, reason for use, dates administered, and dosing information. 
Contact the Medical Monitor for any questions on concomitant or prior therapy. 
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6.8.1 
Permitted Medicines  
The only permitted medicines are the following: 
• Medication to prevent or treat concomitant diseases or to treat adverse effects of investigational 
intervention are allowed unless otherwise specified in the sections below. 
• Any medicines that are considered necessary to protect the participant’s welfare in emergencies 
may be given at the Investigator’s discretion, regardless of if it results in a protocol deviation. 
• SARS-COV-2 vaccination: 
In case a participant is vaccinated for SARS-COV-2 during the study treatment period, the 
following actions should be considered: 
o Administer only approved vaccines. 
o Nonreplicating viral vector-based vaccines and mRNA-based vaccines are not 
considered live attenuated vaccines (exclusion criterion #16) and can be 
administered during this clinical study. Any future live attenuated vaccine for 
SARS-COV-2 is prohibited within 28 days prior to the first dose of study 
intervention and up to 90 days after EOT. 
o Report all SARS-COV-2 vaccine names, and if available, the manufacturer on the 
ConMed page of eCRF. 
6.8.2 
Medications to be Used with Caution with Xevinapant or 
Placebo  
Drugs With a Known Risk of QTc Prolongation 
The potential of xevinapant to prolong the QTc interval has not yet been fully characterized, 
therefore caution should be exercised when using xevinapant with drugs having a known risk of 
QTc prolongation (refer to drug’s product information or Arizona Center of Education and 
Research Therapeutics database at website: http://www.crediblemeds.org). Monitoring of 
electrolyte levels is strongly recommended. 
Other Drugs to Be Used Under Close Medical Monitoring 
• Drugs that have a narrow therapeutic range or are sensitive substrates of P-gp, CYP2Cs (2C8, 
2C9, 2C19), 2B6 or 1A2 are recommended to be used under close medical monitoring. Some 
CYP3A substrates (not prohibited as per Section 6.8.3) also require close monitoring. Their 
metabolism or transport may be modified by xevinapant resulting in potential increased safety 
events or decreased efficacy. Commonly used drugs are listed below (Table 10 and Table 11). 
Note that this is not an exhaustive listing; for other drugs metabolized by CYP3A, 2Cs, 2B6, 
1A2, or transported by P-gp, refer to the recommendations of the product information. 
 
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Table 10 
Anesthetic and Analgesic Drugs to be Used with Xevinapant under Close 
Medical Monitoring  
Drug 
International Nonproprietary Name 
Anesthetic 
Alfentanil 
 
Systemic lidocaine 
 
Vecuronium 
Analgesic 
Fentanyl 
 
Morphine 
• For alfentanil and fentanyl: risk of DDI due to inhibition of CYP3A4/5 and P-gp by xevinapant. 
The clinical impact is a potential increased exposure, resulting in exacerbated clinical effects of 
alfentanil and fentanyl at standard doses. 
• For lidocaine and vecuronium: risk of DDI due to inhibition of P-gp by xevinapant which might 
potentiate the effects of anesthetic drugs. If such drugs must be included in an anesthetic 
protocol, starting and maintenance doses should be carefully considered. 
Table 11 
Other Drugs to be Used with Xevinapant Under Close Medical 
Monitoring  
International Nonproprietary Name 
International Nonproprietary Name 
Aliskiren 
Hydroxyzine 
Apixaban 
Lamotrigine 
Clopidogrel 
Ondansetron (allowed alternative: dolasetron, granisetron, tropisetron, 
palonosetron) 
Colchicine 
Posaconazole (systemic) 
Dabigatran 
Riociguat 
Digoxin 
Valproic Acid 
Lansoprazole 
 
The metabolism and transport of the above listed drugs occurs through CYP3A4/5, CYP2Cs and/or 
P-gp. As per their product information, the clinical relevance of their co-administration with 
inhibitors or inducers of such enzymes and transporters is difficult to anticipate. In view of the in 
vitro DDI profile of xevinapant, the activity and risk of toxicity of these drugs may be increased 
when co-administered with xevinapant. 
Gastric Mucosal Protectants 
Gastric mucosal protectants, if needed, cannot be taken within 2 hours before or 2 hours after 
xevinapant intake because their concomitant intake may decrease the absorption of xevinapant. 
Participants must be instructed accordingly. 
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6.8.3 
Prohibited Medicines  
• Participants are prohibited from receiving the following therapies during the screening and 
treatment phases: anticancer systemic chemotherapy, anticancer immunotherapy, or anticancer 
biological therapy not specified in this protocol. 
• Use within 14 days prior to randomization or requirement for ongoing treatment with any 
drug(s) on the prohibited medication list in Sections 6.8.3.1, 6.8.3.2, and 6.8.3.3 or within 
3 days prior to randomization for the drugs in Section 6.8.3.4 is an exclusion criterion. 
• Treatment with an investigational agent other than xevinapant / placebo or use of an 
investigational device within 4 weeks of the first dose of study treatment or during study 
treatment. 
• In case of unavoidable concomitant administration of a prohibited medicine during 
investigational treatment, the need for suspension or discontinuation of xevinapant / placebo 
must be discussed beforehand with the Sponsor. 
• Live vaccines within 28 days prior to the first dose of study intervention and up to 90 days after 
EOT are prohibited. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; 
however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not 
allowed. 
• The use of hematopoietic growth factors is prohibited during the concomitant RT phase of 
the study. 
• Other preparations and medications such as those listed in the below sections are strictly 
prohibited in combination with xevinapant / placebo. 
6.8.3.1 
Recombinant Human Erythropoietin and Derivates  
Recombinant human erythropoietin is not allowed throughout the entire duration of the study. 
Nonclinical and clinical studies showed that autocrine or paracrine erythropoietin signaling can 
enhance cancer invasion in SCCHN and negatively affect patient outcome in terms of OS and 
localregional PFS (Henke 2003, Lambin 2009). 
6.8.3.2 
Food and Herbal Preparations  
• Grapefruit juice and grapefruit-containing products (P-gp inhibitors, may lead to increased 
xevinapant exposure) are not allowed during the treatment phase. 
• St John’s Wort (= Hypericum perforatum, millepertuis) and St John’s Wort-containing products 
(P-gp inducers, may lead to decreased xevinapant exposure) are not allowed during the 
treatment phase. 
• Any traditional Chinese medication with approval for use as anticancer treatment (regardless of 
the type of cancer) will not be permitted. Traditional Chinese medicines for indications other 
than anticancer treatment, such as supportive care, may be administered at the discretion of the 
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metabolized into the active drug. Commonly used drugs that are CYP3A4/5 sensitive substrates 
are listed in Table 13. Note that this is not an exhaustive listing; refer to the product information 
for other drugs that are narrow therapeutic index drugs or sensitive substrates of CYP3A. 
Table 13 
Examples of Prohibited CYP3A4/5 Sensitive Substrates with Xevinapant  
International Nonproprietary Name 
Avanafil 
Lurasidone 
Budesonide 
Maraviroc 
Buspirone 
Midazolam 
Conivaptan 
Naloxegol 
Darifenacin 
Nisoldipine 
Darunavir 
Quetiapine 
Dasatinib 
Saquinavir 
Dronedarone 
Sildenafil 
Ebastine 
Simvastatin 
Eletriptan 
Sirolimus 
Eplerenone 
Tacrolimus 
Everolimus 
Ticagrelor 
Felodipine 
Tipranavir 
Ibrutinib 
Tolvaptan 
Indinavir 
Triazolam 
Lomitapide 
Vardenafil 
Lovastatin 
 
Source: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers (accessed 16 March 2022). 
6.8.4 
Other Interventions  
6.8.4.1 
Nutritional Support  
All participants must be screened for nutritional risk and early enteral nutrition. Nutrition status 
must be evaluated as indicated in Table 1, Table 2, and Table 4. 
Maintaining adequate nutritional support is essential during the radiotherapy and monotherapy 
period. Participants must receive dietary advice to help maintain their weight during the course of 
radiotherapy. In case of important swallowing difficulties and/or weight loss exceeding 5% to 10%, 
a feeding tube is recommended, either a percutaneous endoscopic gastrostomy or nasogastric tube 
can be placed. The Investigator needs to ensure that the participant has access to nutritional 
support. 
A feeding tube is mandatory if the participant has Grade ≥ 3 dysphagia. 
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6.8.4.2 
Dental Care  
Participants 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 (NCCN v3 2021). 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 in 
Appendix 9. 
6.8.4.3 
Pain  
The management of pain should be done according to severity and recommended drugs as per 
institutional guidelines. Review Table 10 before using concomitant medications. 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1 
Discontinuation of Study Intervention  
Study intervention (i.e. xevinapant / placebo, and IMRT) must be discontinued under the following 
circumstances: 
• Disease relapse (see DFS definition in Section 3). 
• Participant withdrawal of consent for treatment. 
• Participants may voluntarily discontinue one or several of the study interventions at any 
time. If such discontinuation occurs, every effort should be made by the Investigator to 
determine the primary/underlying reason for this decision, which should be recorded in the 
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 intervention due to AEs must be treated and 
followed up for these AEs according to standard medical practices. 
• Any protocol deviation that results in a significant risk to the participant’s safety, only after 
discussion with Sponsor. 
• Noncompliance that is deemed by the Investigator or the Sponsor to compromise participant 
safety or study integrity. 
• Pregnancy (Section 8.3.4). 
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• 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. 
• Initiation of any other cancer therapy. 
• Early study termination by the Sponsor, Steering Committee, the Investigator, the IEC/IRB, or 
the Regulatory Agencies. 
The primary reason for study intervention discontinuation must be recorded in the eCRF. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
If study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for safety and efficacy (see DFS and OS follow-up periods in Table 4 and Table 5). The 
SoA indicates data to be collected at the time of discontinuation of study intervention (Table 2 - 
EOT visit) and follow-up and for any further evaluations that must be completed. In case of 
premature treatment discontinuation, the first visit in the DFS FU period starts 1 month after EOT 
visit. Efficacy assessments including HRQOL will continue to be performed in case of premature 
discontinuation from study intervention in the absence of a DFS event. 
7.1.1 
Temporary Discontinuation  
See Section 6.5.1.2 (xevinapant / placebo) and Section 6.5.2.3 (RT) for further guidance on 
temporary discontinuation of treatment. 
7.2 
Participant Discontinuation/Withdrawal from the Study  
• A participant may discontinue from the study at any time, at his/her own request or at the 
discretion of the Investigator for safety, behavioral, compliance, or administrative reasons. 
• Participants may voluntarily withdraw consent for study participation at any time. If such 
withdrawal occurs, every effort must be made by the Investigator to determine the 
primary/underlying reason for this decision which must be recorded as reason in the form in the 
eCRF i.e. if the underlying reason for the decision is toxicity (e.g. AE) this must be recorded as 
such and the Investigator has to follow-up the participant until the AE is resolved. 
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• At the time of study discontinuation, if possible, a discontinuation visit will be conducted, as 
listed in the SoA. The SoA specifies the data to collect at study discontinuation and follow-up, 
and any additional evaluations that need to be completed. 
• If the participant revokes consent for the study, any data collected up to that point may still be 
used, but no future data can be generated, and any biological samples collected will be 
destroyed. 
• A participant has the right at any time to request destruction of any biological samples taken. 
The investigator will document this in the site study records and the eCRF and inform the 
Sponsor. The samples will be destroyed. 
• Premature discontinuation from the study can also be triggered by: 
o Participant lost to follow-up (Section 7.3) 
o Death 
o Early study termination by the Sponsor, Steering Committee, the Investigator, the IEC/IRB, 
or the Regulatory Agencies 
• Should a participant be withdrawn from the study, EOS assessments must be performed prior 
to any further therapeutic intervention, whenever possible. Results of these assessments must 
be recorded in the eCRF, together with a description of the reasons for study discontinuation. 
Participants who prematurely discontinue will not be replaced. 
7.3 
Lost to Follow-Up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions will be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wants to or should continue in the study. 
• Before a participant is deemed “lost to follow-up”, the Investigator or designee will make every 
effort to regain contact with the participant: 1) where possible, make 3 telephone calls; 2) if 
necessary, send a certified letter (or an equivalent local method) to the participant’s last known 
mailing address, and 3) if a participant has given the appropriate consent, contact the 
participant’s general practitioner or caretaker (where allowed by local regulations) for 
information. These contact attempts will be documented in the participant’s medical record. 
• If the participant continues to be unreachable, he/she will be deemed as “lost to follow-up”. 
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8 
Study Assessments and Procedures  
• Study assessments and procedures and their timing are summarized in the SoA. It may be 
necessary to perform these assessments at unscheduled timepoints if deemed clinical necessary 
by the Investigator. 
• Additional survival follow-up information may be collected from participants or their family 
doctor between routine study visits upon Sponsor request to check on health status and collect 
survival information. 
• No protocol waivers or exemptions are allowed. 
• Immediate safety concerns are discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All screening evaluations will be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all participants screened, to confirm eligibility, and if applicable, record reasons for screening 
failure. 
• 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 
Appendix 6). The IMRT plan must be approved by the RT-QA Review Center prior to the start 
of the IMRT. 
• Prior to performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will obtain written informed consent as specified in Appendix 6. 
• Procedures conducted as part of the participant’s routine medical care (e.g. blood count) and 
obtained before signing of the ICF may be used for screening or baseline purposes provided the 
procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA. 
No more than 60 mL of blood may be drawn in a 24-hour period, and no more than 130 mL of 
blood in a 4-week period. 
Where allowed by local law/regulations, samples collected during this clinical study may be 
transferred to a biobank and used for future research outside the clinical protocol when additional 
consent for this purpose is given. Transfer to the biobank will be documented and any testing of 
coded biobank samples will not be reported in the CSR. 
The long-term storage of samples and imaging data after study completion for future research may 
be performed with all sample types collected in the study (e.g. PK, pharmacogenomics, 
biomarkers, or immunogenetic) if the participant consents to optional future medical research. 
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Order of Assessments 
• The participants should be given the QOL questionnaires (Section 8.1.5) to be completed at the 
scheduled visit before other clinical assessments are conducted. 
• ECG readings must be taken prior to blood collection. 
Screening Period 
Participants will be screened between Days -28 and -1, prior to randomization (Day 1 [-3 days]). 
Activities and procedures to be performed at Screening are detailed in the SoA (Section 1.3). 
Screening-specific procedures include: 
• Demography: birth year, age at informed consent, sex, race (only where allowed by local 
law/regulations), and ethnicity. If ≥ 70 years, G8 questionnaire to be completed. 
• Medical history: disease history, previous illness and surgeries (e.g. all during the past year and 
only major ones prior to that), concomitant illness, relevant medication, therapies stopped or 
changed at entry into the study, allergies, tobacco use, alcohol use. 
• Audiometry: not required if one of the other high-dose cisplatin ineligibility inclusion criteria 
are met (Section 5.1). 
• Eastern Cooperative Oncology Group Performance Status: assessed at Screening to assess 
eligibility (Section 5.1) and then assessed according to the SoA (Section 1.3). 
• Tumor staging (using the AJCC/TNM Staging System, 8th Ed.) based on radiological imaging 
and pathological assessment after SCCHN surgery. 
• SCCHN surgery details: resection margins (R), positive nodes, risk factors (extra-capsular 
extension/ positive margin). 
• Results from the central laboratory should be used for defining participant eligibility during 
Screening, except for: 
o HIV test that may be performed by a local laboratory within 2 weeks before ICF signature 
(Section 8.2.4). 
o HPV status by p16 IHC (mandatory for OPC, optional for other tumor locations) that may 
be obtained locally (Section 8.2.4.1). 
o SARS-CoV-2 PCR and/or antigen test if required (Section 8.2.4). 
8.1 
Efficacy Assessments and Procedures  
Tumor assessments will be completed using a combination of clinical, radiological and, if 
appropriate, fiberoptic endoscopy and pathological assessments, integrating in case of a potential 
tumor relapse, a direct pathologic ascertainment. 
Radiographic and clinical evaluations will be conducted with the same schedule in both treatment 
arms (Table 1, Table 2, Table 4, and Table 5). For radiological assessments, RECIST 1.1 criteria 
adapted for participants with no residual disease at baseline, including for determination of nodal 
disease relapse will apply (adapted from Eisenhauer 2009). See Appendix 7 for further details. 
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At baseline, tumor assessment will require CT scan and/or MRI for head and neck and CT scan of 
chest. 18F-FDG-PET is required at EOT (Table 2), and at any time if disease relapse is suspected 
but not proven by CT and/or MRI, or at the Investigator’s discretion. 
In addition, the most recent pre-surgery diagnostic/staging CT and/or MRI scans done as a part of 
SoC should be submitted to the IRC vendor, if available, as well as any recent pre-surgery or 
baseline PET-CT scan if acquired, to facilitate IRC assessment of any potential macroscopic 
residual disease at baseline.   
Tissue (biopsy) confirmation of disease is required for all local and regional suspected disease 
relapse unless medically contraindicated. When disease relapse is suspected by distant metastasis, 
confirmation of pathology is recommended in case of solitary metastasis (especially in the lung) 
unless medically contraindicated. All biopsies will also be reviewed centrally as part of the 
independent review process (Section 8.1.4). For cases where biopsy is contraindicated or the 
medical risk assessed as too high, radiological assessment by RECIST 1.1 alone will apply 
(Appendix 7). Disease relapse on imaging must be confirmed in the absence of histopathological 
evidence. 
After unequivocal disease relapse, participants will enter the OS follow-up period at time of the 
confirmation of the event (Section 1.3). 
8.1.1 
Radiological Assessment  
For each participant, the same imaging modality for head and neck and for chest must be used 
throughout the study. The schedule of collection of IV contrast-enhanced CT scan and/or MRI of 
head and neck (including coverage of the orbits), CT scan of the chest and 18F-FDG-PET scan 
(from the skull base to proximal upper legs) is provided in Table 1, Table 2, Table 4, and Table 5. 
Any other site of suspected disease should also be imaged. 
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. 
If an off-schedule imaging assessment is performed because relapse is suspected or for other 
reasons, subsequent assessments should be performed in accordance with the original imaging 
schedule. 
For all participants, radiological tumor assessments are to continue until unequivocal disease 
relapse by imaging according to RECIST 1.1 adjusted for a study wherein no residual disease is 
expected at baseline, if applicable, or by pathology. Tumor assessments will be performed 
according to the original schedule regardless of premature treatment discontinuations or treatment 
delays. 
All images will also be reviewed centrally as part of a centralized independent review. Further 
details will be in an Imaging Charter provided for this study. 
The Sponsor may discontinue image transfer to vendor once no further analyses by IRC assessment 
are planned. 
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8.1.2 
Clinical Assessment  
The clinical assessments will include a detailed description of tumor extension and/or nodal 
extension for palpable nodes in the neck. If appropriate, this should be completed by a fiberoptic 
endoscopy (by a Head and Neck surgeon) under general anesthesia and biopsy. 
For all suspected disease relapse that is detected clinically (by endoscopy), but is not visible on 
radiographic imaging, an objective evidence supporting disease relapse must be collected and 
submitted to IRC. Tissue (biopsy) confirmation of disease is required for all local and regional 
suspected relapse of disease unless medically contraindicated. Photographs and reports from 
endoscopy procedure should be collected by the site (if available) and both should be submitted to 
IRC for central review. Please refer to the Imaging Charter for detailed information. 
It is recommended that all new distant solitary lesions suspicious for metastatic disease are also 
biopsied and pathologically confirmed. Prior to performing biopsy, concomitant diseases, location 
of relapse, coagulation status and concomitant medications must be reviewed for any 
contraindications in line with local practice. 
During the follow-up period the participants will undergo ear, nose, and throat examination, as per 
the schedule presented in Table 4 and Table 5. Fiberoptic endoscopy, if appropriate, will be done 
as part of these clinical examinations. 
Any treatment intervention in relation to the disease under study, including biopsies as well as the 
anatomical site(s) and histopathology results must be reported in the eCRF. 
8.1.3 
DFS Events and Definitions  
The reappearance of any lesion with squamous histology, or the development of a new lesion with 
squamous histology, will be considered a DFS event. 
 
 In the situation where a 
single pathologic node is driving the progression event and there is no biopsy data, continuation 
of treatment/follow-up and confirmation by a subsequent exam should be contemplated. If it 
becomes clear that the “new node” has not resolved, or has significantly increased in size, and 
truly represents PD, the date of PD would be the date the new node was first documented 
(Schwartz 2016). 
 
A DFS event is defined as follows: 
• Local relapse is present if recurrent tumor is found at the site of original tumor location. Tumor 
reappearing within the radiation field (inside the GTV) will be considered local relapse. 
 
 
 The date of relapse is 
the date of positive pathology, or the date of imaging detection (including by PET scan, if 
earliest) subsequently confirmed by biopsy, whichever is first. 
• Regional relapse is present if recurrent tumor is found at the regional lymph node basins (e.g. 
neck nodes). 
 
 
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The date of relapse is the date of positive pathology, or the date of imaging detection (including 
by PET scan, if earliest) subsequently confirmed by biopsy, whichever is first. 
• Distant metastasis is defined as a new lesion of squamous cell histology identified outside the 
radiation field (outside the PTV) or draining lymph nodes. When disease relapse occurs for 
distant metastases, confirmation of distant metastasis by pathology is strongly recommended in 
case of solitary lesions (especially in the lung) unless biopsy is medically contraindicated or the 
medical risk of biopsy assessed as too high. A solitary speculated lung mass/nodule is a second 
primary neoplasm and is not a disease relapse event unless proven otherwise by biopsy, i.e. 
tumor of squamous cell histology. Multiple lung nodules/masses are considered distant 
metastases and constitute a disease relapse event unless proven otherwise by biopsy, i.e. tumor 
of non-squamous cell histology. The date of relapse is the date of positive pathology, or the date 
of imaging detection (including by PET scan, if earliest) subsequently confirmed by biopsy, 
whichever is first. 
• Note: For cases where no histopathological assessment but tumor assessment by imaging is 
available, any new tumor lesion will be considered a relapse. RECIST 1.1 criteria adapted to a 
study where there is no residual disease at study entry will be applied for determination of nodal 
lesions to constitute local, regional or distant relapse. Any lesion of non-squamous origin is 
considered a second primary cancer. In case of a second primary cancer, DFS data collection 
should continue as per SoA (Table 2, Table 4, and Table 5), regardless of start of new anticancer 
therapy. 
Good clinical judgment must be used when deciding whether a biopsy is required. If any of the 
following conditions are met, a biopsy must be done, unless medically contraindicated or medical 
risk of biopsy deemed too high: 
• New lesions on imaging or clinical exam 
• Suspicious mucosal changes 
• Newly enlarged, regional lymph nodes on clinical exam or imaging 
• Areas of unexplained new PET positive FDG-uptake 
If a biopsy is not performed a rationale must be entered in the eCRF. 
8.1.4 
Endpoint Assessment by IRC  
An IRC will perform an independent assessment based on all efficacy imaging reading together 
with central independent review of histopathology. DFS supplementary 2 analyses (Table 19) will 
use the IRC data for the purpose of significance testing with regards to demonstrate the 
hypothetical isolated treatment effect as assessed by an IRC, which is implemented to minimize 
the assessment bias. Further sensitivity analyses will evaluate the robustness of the DFS main 
analysis with regards to the assessor of DFS. 
Hence, all study imaging performed, including any off-schedule imaging, and all histopathological 
materials should be submitted to the designated vendor(s) promptly after acquisition. 
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Further details will be described in the Imaging Charter, the Independent Review Charter and 
histopathology guidelines provided for this study. 
8.1.5 
Quality of Life  
HRQL outcomes are relevant to SCCHN patients, and improvements in their QOL is a significant 
unmet need. SCCHN can directly affect HRQL due to several side effects of treatment and disease 
(Liao 2019). All SCCHN patients have to endure QOL limiting surgery and/or very burdensome 
medical treatments. Surgery is associated with severe negative impact on patients’ lives, often 
resulting in long-term pain, impairment of social functioning and severe depression (Hernandez-
Vila 2016). Nonsurgical treatments, especially platinum-based CRT, are extremely difficult for 
patients to endure, due to extensive negative side effects (Oun 2018). Thus, improvement in 
therapy to enhance treatment outcomes without generating incremental detriment to patients’ QOL 
must be priorities in the advancement of SCCHN therapy. 
Multiple PRO instruments have been used in clinical research to capture different aspects of the 
disease burden. A systematic literature review of QOL measures in SCCHN performed between 
1990 and 2010 identified 57 different disease-specific HRQL measures, another publication has 
counted a total of 250 different questionnaires which have been used within this indication with 
varying degrees of specificity including measures which assess individual symptoms such as 
swallowing (Ojo 2012). The EORTC QLQ-HN35 used in conjunction with the corresponding core 
cancer module (EORTC QLQ-C30) emerged as the most frequently used instrument for a 
prospective assessment of HRQL in head and neck cancer patients (Ojo 2012) and have been 
selected as most relevant for this study population. In addition, the PGIS and PGIC will be 
included. The PGIS provides a method for classifying participants’ perception of overall symptom 
severity and the PGIC provides a method for classifying participants’ perception of overall 
symptom change over a specified time period, both can be used in exploratory and psychometric 
analysis. 
The FDA has identified symptomatic AEs as a critical component to patient focused drug 
development. Among the recommendations, systematic assessment of symptomatic AEs by the 
patient can increase understanding of the patient experience while on treatment and complement 
clinician reporting (Kluetz 2016). The NCI has created a patient-reported outcomes version of the 
CTCAE to assess the patient perspective on symptomatic AEs (PRO CTCAE). The PRO CTCAE 
is a patient-reported measure that ascertains in real time the frequency, severity, interference, and 
presence/absence of symptomatic toxicities that can be meaningfully reported from the patient 
perspective. Research indicates the psychometric properties including validity, reliability, 
responsiveness, and test-retest reliability, are acceptable. 
The proposed combination of HRQL instruments is informed by the purpose of capturing both 
potential treatment-specific, cancer-specific and SCCHN-specific dimensions through 
nonpreference-based questionnaires as well as the preference-based EQ-5D-5L to inform health 
economic modeling for health state utility estimates. 
Participants should read and complete the PRO instrument independently. All PRO assessments 
should be completed by the participants as indicated in the SoA. Whenever possible, the PRO 
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assessments will be completed prior to administration of study intervention. The CRO and the 
Sponsor will review compliance rates on a regular basis. PROs will not be reviewed or used to 
inform care decisions nor for safety purposes. 
Whenever possible and as appropriate, the PRO instruments should be completed in the following 
order: EQ-5D-5L, EORTC QLQ-C30, EORTC QLQ-HN35, PGIS, PGIC, patient perception of 
side effects (Item Library Q168), and PRO CTCAE. 
The following will be administered electronically: 
EQ-5D-5L 
The EQ-5D-5L is a 6-item instrument developed by the EuroQol Group as a measure of 
health-related quality of life that can be used in a wide range of health conditions and treatments. 
The EQ-5D-5L consists of a descriptive system (5 items) and a single item EQ VAS. The 
descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression. The EQ VAS records the participant’s self-rated health on a vertical VAS. 
The EQ-5D-5L has 5 response categories: no problems, slight problems, moderate problems, 
severe problems, and extreme problems. The participant is asked to indicate his/her health state by 
ticking the box next to the most appropriate statement in each of the 5 dimensions. The responses 
to each of the 5 dimensions (ranging from 1 to 5) are summarized into a 5-digit profile, which can 
be converted into a preference-weighted index value and is a key component for discussions with 
access decision makers. 
EORTC QLQ-C30 
The EORTC QLQ-C30 is a cancer-specific health-related QOL questionnaire that has been widely 
used in clinical studies (Kluetz 2016) consisting of 5 function domains and 8 symptoms for a total 
of 30 items. Development and validation of the EORTC QLQ-C30 has been well documented as 
a reliable and valid measure of QOL in cancer patients (Aaronson 1993) with widespread use in 
Europe and the US. 
EORTC QLQ-HN35 
The EORTC QLQ-HN35 is a disease-specific module capturing HRQL dimensions that affect 
head and neck cancer patients specifically. It is composed of 7 symptom scales, 6 symptom items, 
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. Large international samples 
(N = 662) indicate the reliability and validity of the instrument (Bjordal 2000). 
PGIS 
The PGIS is a single, global item assessing the participant’s perception of overall symptom 
severity, using a 5-point scale from “none” to “very severe.” The PGIS provides a method for 
classifying participants as having improved, declined, or not having changed for use in exploratory 
and psychometric analysis, and to evaluate the sensitivity and responsiveness of individual 
symptom items and interpret scores on the PRO instruments. 
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PGIC 
The PGIC is a single, global item assessing the participant’s perception of overall symptom 
change. Participants will rate how their symptoms have changed since treatment initiation, using 
a 5-point scale from “much worse” to “much better.” The PGIC provides a method for classifying 
participants as having much better, much worse, or unchanged symptoms over a particular time 
interval for use in exploratory and psychometric analysis, and to evaluate the sensitivity and 
responsiveness of individual symptom items and interpret scores on the PRO instruments. 
Frequency of Assessment: EQ-5D-5L 
• At the start of each cycle starting with Cycle 1: C1D1, C2D1, C3D1, C4D1, C5D1, C6D1 
• At EOT visit 
• At 12-month follow-up visit 
• At 24-month follow-up visit 
• At 36-month follow-up visit 
• At 48-month follow-up visit 
• At 60-month follow-up visit 
• Within 7 days of entering OS follow-up due to DFS event 
Frequency of Assessment: EORTC QLQ-C30, EORTC QLQ-HN35, and PGIS 
• At C1D1 
• At C4D1 
• At EOT visit 
• At 12-month follow-up visit 
• At 24-month follow-up visit 
• At 36-month follow-up visit 
• At 48-month follow-up visit 
• At 60-month follow-up visit 
• Within 7 days of entering OS follow-up due to DFS event 
Frequency of Assessment: EORTC QLQ-C30 (Short), EORTC QLQ-HN35 (Short) and 
PGIS 
Patients with LA SCCHN consistently indicate head and neck pain, swallowing, speech, fatigue, 
and sensory problems are impacted by chemoradiotherapy (Curran 2007, Driessen 2018, 
Bottomley 2014). Trends indicate some symptoms, such as head and neck pain and swallowing, 
improve in the short term, but then return to baseline following treatment (Driessen 2018). Given 
the potential variation in symptom experience over the course of treatment, more frequent 
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assessment of key symptoms will be obtained. Head and neck pain (4 items), swallowing (4 items), 
speech (3 items), fatigue (3 items), global health status (2 items) and physical function (4 items), 
will comprise the EORTC QLQ-C30 (short), QLQ-HN35 (short) for a total of 20 items and be 
assessed at the following timepoints along with the PGIS: 
• At C2D1 
• At C6D1 
• At 9-month follow-up visit 
Frequency of Assessment: PGIC 
• At the 12-month follow-up visit 
Patient Perception of Side Effects (Item Library Q168) 
The EORTC provides an item library from which sponsors can select specific items that address 
gaps not addressed in the established measures. In order to provide an overall picture of treatment 
side effects, participants will be asked to what extent they have been troubled by side effects from 
not at all to very much. 
PRO CTCAE 
PRO CTCAE consists of 124 items representing 78 symptomatic toxicities and has been validated 
in more than 30 languages. The measure is intended to serve as a complement to the CTCAE used 
for standard reporting in an effort to more accurately reflect the patient experience. 
 
 
 
 
 
 
 
 
 
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Frequency of Assessment: Patient Perception of Side Effects (Item Library Q168) and PRO 
CTCAE 
• At C1D1 
• Weekly starting with C1D8 through C6D15 
• At EOT visit 
The measurement intervals of all questionnaires represent the appropriate balance between 
allowing a comprehensive HRQL assessment of a first-in-class compound across all the 
dimensions included in the proposed questionnaires, a focused assessment of key symptoms, and 
the burden created for the targeted patient population by administering these questionnaires at the 
different time points (and the implied risk of nullifying the analysis due to excessive missing data). 
8.2 
Safety Assessments and Procedures  
The safety profile of the study intervention will be assessed through the recording, reporting and 
analysis of baseline medical conditions, AEs, physical examination findings, vital signs, 
electrocardiograms, and laboratory tests. 
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3. 
8.2.1 
Physical Examinations  
• A complete physical examination will include, at a minimum, assessments of the brief physical 
examination as well as neurological systems. 
• A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, abdomen (liver, spleen, and pancreas) as well as the head, mouth, and 
neck area. 
• Investigators will pay special attention to clinical signs related to previous serious illnesses and 
AEs requiring a dose modification (Section 6.5). 
• Investigators will report findings including late onset AESIs (Section 8.3.7) in the irradiated 
areas during the DFS and OS FU periods. 
8.2.2 
Vital Signs  
• Blood pressure and participant’s position, pulse, respiratory rate, temperature and location of 
measurement, weight, and height (at Baseline only) will be measured and recorded according 
to the SoA (Section 1.3). 
• Blood pressure and pulse measurements will be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g. television, cell phones) and measured 
with an automated device. Manual techniques will be used only if an automated device is not 
available. 
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8.2.3 
Electrocardiograms  
• Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically measures heart rate, PR, RR, QRS, and QT. If QTcF is not automatically 
measured, it can be calculated separately.  
• A standard single 12-lead ECG will be recorded after 10 minutes of supine rest according to the 
schedule shown in Table 15. 
Table 15 
ECG Collection Plan  
Study Visit or Cycle 
Day 
Time Relevant to Dosing 
Screening 
-28 to -1 
NA 
Cycle 1 
1 
predosea 
0.5-4 h postdoseb 
Cycle 1 
8 
predosea 
0.5-4 h postdoseb 
ECG=electrocardiogram, NA=not applicable. 
a 
To be performed prior to all predose blood collection. 
b 
To be performed prior to blood collection for PK. 
If several ECGs (scheduled and unscheduled) are performed during Screening, the latest results 
must be recorded and used. 
• 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 relevant to QT interval (e.g. QTcF prolongation > 30 ms 
compared to baseline, or QTcF interval > 500 ms, Torsade de Pointe, ventricular tachycardia, 
ventricular fibrillation, flutter) or any other new clinically significant cardiac abnormality, 
triplicate ECG readings will be performed including the already abnormal ECG reading. If the 
abnormal ECG finding is confirmed after triplicate ECG readings, the participant must be referred 
to a local cardiologist. 
Significant QTcF prolongation is defined as an interval > 500 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 8): 
• The treatment with xevinapant/ placebo must be interrupted. 
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• 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 < 480 ms. 
• 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 / placebo 
doses. 
• If the QTcF interval does not return to within 30 ms of baseline or < 480 ms within 14 days, 
xevinapant / placebo must be permanently discontinued. 
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 / placebo 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. 
8.2.4 
Clinical Safety Laboratory Assessments  
• Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 2 
at the time points listed in the SoA. All samples will be clearly identified. 
• The following tests are only performed at Screening: coagulation, HBV, HCV, HIV tests and 
SARS-CoV-2 test (PCR or antigen test). Additional coagulation tests may have to be performed 
prior to tumor biopsy according to local practice. 
• Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will be 
conducted every 3 weeks (C1D1, C2D1, C3D1, C4D1, C5D1 and C6D1) during study 
intervention administration, as well as at the EOT visit. 
• Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will be 
conducted at the end of relevant systemic exposure of the study intervention. 
• Additional tests may be performed at any time during the study, as determined necessary by the 
Investigator or required by local regulations. 
• The tests will be performed by a central laboratory designated by the Sponsor and by a local 
laboratory, according to instructions shown in Table 16. 
• Local laboratory results are only required when central laboratory results are not available in 
time for study intervention administration and/or response evaluation. If a local sample is 
required, it is important that the sample for central analysis is obtained at the same time. 
Additionally, if the local laboratory results are used to make a study intervention decision or 
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response evaluation, the results will be recorded. Also, on CxD1, laboratory assessments 
required to evaluate suitability for study intervention administration may be evaluated on basis 
of local laboratory values. These results will be recorded. 
• The Investigator will review each laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE, unless it does not meet the 
AE definition, as specified in Appendix 8. The laboratory reports will be filed with the source 
documents. 
Table 16 
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 
• 
HIV test if no local results obtained within 2 
weeks before ICF signature 
• 
HPV status by p16 IHC if no available report 
and test not available locally (Section 8.2.4.1) 
• 
HBV/HCV testsa 
• 
Blood hematology 
• 
Blood biochemistry 
• 
Serum pregnancy test 
• 
Urinalysis 
• 
Coagulation  
• 
Local results within 2 weeks 
before ICF signature accepted 
for HIV test 
• 
HPV status by p16 IHC if no 
available report 
• 
SARS-CoV-2 PCR and/or 
antigen test 
• 
Retest of abnormal laboratory 
assessments 
• 
Coagulation as required prior to 
biopsies as per local practice 
CxD1 
All blood hematology, blood biochemistry 
assessments (full panel) and urinalysisb 
mentioned in Appendix 2.   
Laboratory assessments required to 
evaluate suitability for study 
intervention administration: eGFR, 
platelet counts, ANC, hemoglobin, 
ALT, AST, urine pregnancy test 
(pregnancy test at C1D1, C2D1, 
C3D1, C4D1, C5D1, C6D1 and 
EOT). 
All visits after 
randomization, except 
CxD1 
Blood hematology, blood biochemistry (minimum 
panel), and urinalysisb assessments (Appendix 2), 
to be performed according to schedule presented 
in Table 1 and Table 2. 
Urine pregnancy test, when 
applicable. 
Coagulation as required prior to 
biopsies as per local practice. 
ALT=alanine transaminase, ANC=absolute neutrophil count, AST=aspartate aminotransferase, CxDx=Cycle x Day x, 
eGFR=estimated glomerular filtration rate, IHC=immunohistochemistry, HBV=hepatitis B virus, HCV=hepatitis C 
virus, HIV=human immunodeficiency virus, HPV=human papillomavirus. 
a: Interpretation of HBV/HCV tests results will be further clarified in the Laboratory Manual. 
b: Dipsticks provided by central laboratory; test done locally. In case of abnormal result, microscopic evaluation at 
central laboratory. For screening and EOT visit, urinalysis (dipstick and microscopic evaluation) done at central 
laboratory 
8.2.4.1 
HPV Status in Participants with OPC  
• In participants with OPC, tumor HPV status should be determined by p16 IHC. 
• For OPC participants, p16 expression 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]. 
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• 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 status has been communicated to the site. 
• The results of existing local data must be captured on the appropriate eCRF upon enrollment 
into the study after the participant has signed the ICF. 
• For non-OPC participants, if tumor HPV status is available, this can also be captured on the 
eCRF as well; for these participants if no result is available, it is not needed to have the HPV 
status assessed. 
8.2.5 
External Data Monitoring Committee  
The external DMC will perform a safety review after 12 participants have been randomized, 
treated, and followed up until the end of the combination therapy period and hereafter every 4 
months during recruitment and twice a year after recruitment has been completed if not otherwise 
requested earlier by the Sponsor or the external DMC. The external DMC will also take into 
consideration available PK data when assessing safety. For further details, refer to the external 
DMC Charter. 
8.2.6 
Patient Diary  
Xevinapant / 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 of PK sampling C1D1, C1D2, C1D8, C2D2, C2D8, C4D1, C5D1, and C6D1 participants 
must take their doses at the hospital, where the administration of xevinapant / placebo will be 
supervised and recorded by the medical staff both in the eCRF and in the patient’s diary. In addition, 
time of last dose taken (at home) prior to xevinapant PK collection (i.e. at C1D7, C2D1, C2D7) 
needs to be recorded in the participant’s diary and reported in the eCRF. On days of PK sampling, 
at C3D8 xevinapant / placebo is taken at home, and the time of last dosing prior to PK sample 
(C3D8) must be recorded both in the eCRF and the patient’s diary. 
The treatment schedule of xevinapant or the matched placebo is presented in Table 1, Table 2, and 
Table 3. Participants will be instructed by the medical staff on how to self-administer 
xevinapant/matched placebo at home. The participant should inform the medical staff of any 
missed or delayed doses. 
The diary will be dispensed to the participants according to the schedule presented in Table 1. 
They will be instructed on how to record xevinapant/matched placebo administration (i.e. date and 
time of the xevinapant/matched placebo intake should be recorded in the diary). 
Participant should record any skipped or miss-timed doses in their diary. 
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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. 
 
 
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8.3 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting  
• The definitions of an AE and a SAE are in Appendix 8. The on treatment and late onset AEs of 
special interest are defined in Section 8.3.7. 
• The Investigator and any qualified designees (e.g. Sub-Investigators) are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE. The 
Investigator remains responsible for following up all SAEs and AESIs as specified in Section 
8.3.2. 
• Requests for follow-up will usually be made via the Sponsor or CRO-designated study team 
member, although in exceptional circumstances the global patient safety department may 
contact the Investigator directly to obtain further information or to discuss the event. 
• The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are in Appendix 8. 
• All AEs and SAEs will be collected from the signing of the ICF until the FU28 visit or until the 
start of next line anticancer therapy, whichever occurs earlier. Late onset AESIs 
(Section 8.3.7.2) and related SAE will be collected until completion of study at the time points 
specified in the SoA (Section 1.3) and for AESIs further detailed in Section 8.3.7. Beyond this 
reporting period, any new unsolicited SAEs that the Investigator spontaneously reports to the 
Sponsor will be collected and processed. 
• All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance will this exceed 24 hours, as indicated in Appendix 8. The Investigator will submit 
any updated SAE data to the Sponsor within 24 hours of it being available using the same 
procedure that was used for the initial report. See Appendix 12 for specific requirements in 
India. 
• Investigators are not obligated to actively solicit information on AEs or SAEs after the end of 
study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study intervention or study participation, the Investigator will 
promptly notify the Sponsor. 
8.3.1 
Method of Detecting Adverse Events and Serious Adverse 
Events  
At each study visit, the participant will be queried on changes in his or her condition. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are in Appendix 8. 
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AE data will be obtained by querying the participant and checking the AESI list (Section 8.3.7) 
and will be based on the physical examination. Particular focus should be on the gastrointestinal 
system, hepatobiliary system, kidneys, pancreas, mucosae in head neck area, skin, and eyes. 
Complete, accurate, and consistent data on all AEs experienced for the duration of the reporting 
period (defined in below sections) will be reported on an ongoing basis in the appropriate section 
of the eCRF. 
All SAEs must be additionally documented and reported using the appropriate Report Form as 
specified in Appendix 8. 
8.3.2 
Follow-up of Adverse Events and Serious Adverse Events  
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and AESIs (as defined in Section 8.3.7), will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-
up (as defined in Section 7.3). Reasonable attempts to obtain this information will be made and 
documented. It is also the Investigator’s responsibility to ensure that any necessary additional 
therapeutic measures and follow-up procedures are performed. Further information on follow-up 
procedures is in Appendix 8. 
8.3.3 
Regulatory Reporting Requirements for Serious Adverse 
Events  
Prompt notification by the Investigator to the Sponsor of an SAE (particularly life-threatening and 
deaths) is essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and Investigators. 
Individual Case Safety Reports will be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators within 15 days. 
An Investigator or Sub-Investigator who receives an Individual Case Safety Report describing a 
SUSAR or other specific safety information (e.g. Emerging Safety Issue Report, summary or 
listing of SAEs/SUSARs) from the Sponsor will review the safety reports and confirm completion 
of this review. This information will be filed it in the Investigator’s Site File, and the IRB/IEC will 
be notified, if appropriate, according to applicable local laws/regulations and site SOPs. 
In this global clinical multicenter study, the Sponsor is in the best position to determine an 
unanticipated problem (as defined in US Regulations 21 CFR 312.66). The Sponsor will 
immediately notify all Investigators of findings that could adversely affect the safety of 
participants, impact the conduct of the study or alter the IRB’s approval/favorable opinion to 
continue the study. An unanticipated problem is a serious adverse event that by its nature, 
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incidence, severity, or outcome has not been identified in the current version of the risk analysis 
report, specified in Section 2.3. 
For details on SAE reporting, see Appendix 8. See Appendix 12 for specific requirements in India. 
8.3.4 
Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants will 
be collected after the start of study intervention and until 6 months after the last administration 
of study intervention. 
• If a pregnancy is reported, the Investigator will record the pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of awareness of pregnancy of 
female participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner). 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. Adverse pregnancy 
outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic 
pregnancy) are considered and reported as SAEs. A spontaneous abortion (occurring at 
< 22 weeks gestational age) or stillbirth (occurring at > 22 weeks gestational age) is always 
considered to be an SAE and will be reported as such. 
• The participant pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant pregnant 
female partner and the neonate, and the information will be forwarded to the Sponsor. 
Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the estimated 
delivery date for a healthy newborn. In case of a congenital anomaly or other illness of the 
newborn, follow-up will continue until the illness has resolved or there is a definite outcome of 
the event. 
• Any poststudy pregnancy related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as specified in Section 8.3.3. While the 
Investigator is not obligated to actively seek this information in former study participants 
pregnant female partner, he or she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will be discontinued 
from study intervention. 
8.3.5 
Cardiovascular and Death Events  
No dedicated collection of cardiovascular TEAEs is planned for this study. Potential 
cardiovascular adverse events will be recorded according to standard TEAE documentation and 
reporting process. Death will not be collected as SAE but only be recorded as outcome of a TEAE. 
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8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs  
The following DREs are common in participants with the underlying study disease (SCCHN) and 
can be serious/life-threatening: 
• Recurrence of the underlying SCCHN 
Because these events are typically associated with the disease under study, they will not be reported 
according to the standard process for expedited reporting of SAEs even though the event may meet 
the definition of a SAE. These events will be recorded as part of the primary endpoint. 
However, the event will be recorded and reported as an AE/SAE (instead of a DRE) as defined in 
Appendix 8. 
8.3.7 
Adverse Events of Special Interest  
For this study, AESI(s) include the following as described in the Sections 8.3.7.1 and 8.3.7.2. The 
reporting of AESIs is specified in Appendix 8 and details on criteria and events are in Appendix 
10.  
Based on emerging safety data collected during the study, changes to the AESI list might be 
required. Should this be the case, an updated list will be included in the Investigator’s Brochure at 
the regular annual update. Thus, Investigators are encouraged to consult the latest version of the 
Investigator’s Brochure when assessing the need to report an AESI. 
All AESIs will be followed up until resolution or stabilization (see Section 8.3.2.). 
The site of monitoring during Treatment Period and DFS Follow-up Visits will be 
in-person/clinic/hospital visits. OS Follow-up visits may be conducted remotely (e.g. by telephone 
calls) if possible (see Table 1, Table 2, Table 4, and Table 5 for visit schedules). For participants 
who enter the OS FU earlier than 28 months after start of treatment (e.g. due to PD), the site of 
monitoring will be in person/clinic/hospital visits up to 28 months after start of treatment or until 
start of next line of anticancer therapy, whichever occurs earlier. 
8.3.7.1 
AESIs During the Treatment Period  
 
 
 
 
 
 
 
 
 
 
 
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Reporting of such events as AESI according to the criteria mentioned above will not have any 
impact on the reporting requirements for other AESIs, SAEs, or SUSARs as defined elsewhere in 
this protocol. 
8.3.7.2 
Late Onset AESIs During the Follow-up Period (After FU28 
Visit up to EOS Visit)  
 
 
 
8.4 
Pharmacokinetics  
• The following PK parameter will be calculated, when appropriate: 
Symbol 
Definition 
Ctrough 
The concentration observed at the end of a dosing interval immediately before next 
dosing (xevinapant) 
Cmax 
Maximum observed concentration during the xevinapant dosing interval 
Whole blood samples of approximately 2 mL per collection for measurement of plasma 
concentrations of xevinapant (including its metabolite(s)). Collection times are specified in the 
SoA. The actual date and time (24-hour clock time) of each sample will be recorded to calculate 
actual time elapsed since the prior dose administration. 
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• The quantification of xevinapant in plasma will be performed using a validated bioanalytical 
method. In addition, metabolite(s) will be measured. Concentrations will be used to evaluate 
the PK of xevinapant and metabolite D-1143-MET1 via population PK approaches. 
• Remaining samples collected for analyses of xevinapant (including its metabolite(s)) 
concentration may also be used to evaluate safety or efficacy aspects related to concerns arising 
during or after the study. 
• Details on processes for collection and handling of these samples are in the Laboratory Manual. 
Retention time and possible analyses of samples after the end of study are specified in the 
respective ICF. 
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 (xevinapant and its metabolite(s)) PK assessments) to prevent analyses of placebo 
participants’ samples and allow PK samples analysis within the samples’ stability period and 
external DMC review. 
 
 
 
 
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8.7 
Immunogenicity Assessments  
Not applicable. 
8.8 
Medical Resource Utilization and Health Economics  
HRU in SCCHN is limited. To generate robust economic information for payers, HRU data 
collection is included for descriptive purposes. Such data will be used for cost-effectiveness 
estimations and budget impact analysis of xevinapant to inform commercial payers and HTA 
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agencies globally. A feasibility study was conducted to ensure the item selection and wording in 
the study eCRF for the purposes of HRU research was appropriate (Gandola 2021). The HRU 
variable collection will focus on, but will not be limited to: 
• Number of hospitalizations by cause 
• Length of hospital stay 
• Number of emergency department visits 
• Number of stays in intensive care units 
• Length of hospital stay in intensive care units 
• Number of surgical reconstructions 
• Number of subsequent systemic cancer treatments 
• Number of participants using feeding tube 
• Duration of feeding tube use 
• Number of speech/language therapy visits 
• Number of swallowing therapy visits 
• Number of dental care visits 
9 
Statistical Considerations  
The study will be considered positive if the primary null hypothesis 𝐻0
𝐷𝐹𝑆 as specified in 
Section 9.1.1 is rejected (see also Table 19, Table 21, Table 22, Figure 6, and Section 9.4.4). 
9.1 
Statistical Hypotheses  
Only the hypotheses for the primary objective DFS (Section 9.1.1) and the secondary objective 
OS (Section 9.1.2) are formally tested for statistical significance in a hierarchical testing procedure 
as outlined in Section 9.4.4. Other statistical tests, confidence intervals and corresponding p-values 
are provided for exploratory purposes only. 
9.1.1 
Primary Objective DFS  
The hypotheses to demonstrate superiority for the primary endpoint DFS comparing Arm A and B 
are: 
𝐻0
𝐷𝐹𝑆: 𝜆𝐴
𝐷𝐹𝑆(𝑡) = 𝜃𝜆𝐵
𝐷𝐹𝑆(𝑡), 𝜃≥1 versus 𝐻1
𝐷𝐹𝑆: 𝜆𝐴
𝐷𝐹𝑆(𝑡) = 𝜃𝜆𝐵
𝐷𝐹𝑆(𝑡), 𝜃< 1, 
where 𝜆𝐷𝐹𝑆(t) represents the hazard at time 𝑡 and 𝜃 the unknown constant of proportionality of 
hazards in the treatment arms corresponding to the hazard ratio of DFS. 
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9.1.2 
Secondary Objective OS  
The hypotheses to demonstrate superiority for the secondary endpoint OS comparing arm A and 
B are: 
𝐻0
𝑂𝑆: 𝜆𝐴
𝑂𝑆(𝑡) = 𝜃𝜆𝐵
𝑂𝑆(𝑡), 𝜃≥1 versus 𝐻1
𝑂𝑆: 𝜆𝐴
𝑂𝑆(𝑡) = 𝜃𝜆𝐵
𝑂𝑆(𝑡), 𝜃< 1, 
where 𝜆𝑂𝑆(t) represents the hazard at time 𝑡 and 𝜃 the unknown constant of proportionality of 
hazards in the treatment arms corresponding to the hazard ratio of OS. 
9.2 
Sample Size Determination  
A total of approximately 700 participants will be randomly assigned to study intervention. The 
primary DFS analysis to demonstrate superiority of Arm A compared to Arm B is planned when 
409 events for the DFS main analysis are reached. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.3 
Analyses Sets  
The analysis sets are specified below. 
Analysis Set 
Description 
SCR 
All participants, who provided informed consent, regardless of the participant’s 
randomization and study intervention status in the study. 
FAS 
The FAS will include all randomized participants. 
SAF 
All participants, who were administered any dose of any study intervention.  
PK 
All participants, who receive at least one dose of xevinapant, have no relevant 
protocol deviations or important events affecting PK, and provide at least one 
measurable postdose concentration. 
FAS=full analysis set, PK=pharmacokinetics, SAF=safety analysis set, SCR=screening analysis set. 
9.4 
Statistical Analyses  
Analysis of all data will be performed by the Sponsor or its designee. The results of all study parts 
will be reported in the clinical study report. Details of the analyses of efficacy, safety, PK, and 
HRQOL will be presented in the Integrated Analysis Plan, which will be finalized before the 
database is locked for analysis. 
To provide overall estimates of treatment effects, data will be pooled across study centers. The 
factor ‘center’ will not be considered in statistical models or for subgroup analyses due to the high 
number of participating centers in contrast to the anticipated small number of participants 
randomized at each center. 
In general, continuous variables will be summarized using number (n), mean, median, standard 
deviation, minimum, and maximum. Time-to-event data will be summarized based on Kaplan-
Meier estimates, including but not limited to median (and 95% CI), frequency of participants with 
events, at risk, rate (and 95% CI) at predefined timepoints. Categorical variables will be 
summarized using frequency counts and percentages. Proportions are calculated based on the 
number of participants in the analysis set of interest, unless otherwise specified in the Integrated 
Analysis Plan. If not explicitly stated, no imputation is used in the analyses. All safety and efficacy 
endpoints will be summarized by treatment arm. 
9.4.1 
Efficacy Analyses  
All analyses on efficacy endpoints are primarily done on the FAS. Participants will be analyzed 
according to the treatment assigned at randomization as per the ITT principle. 
Details on the analyses for primary and key secondary efficacy estimands are shown in Table 19. 
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Estimand 
 
Reference 
#  
Category 
Statistical Analysis 
Use the hypothetical strategy for the intercurrent event ‘Start of 
subsequent anticancer therapy’, i.e. participants who started 
subsequent anticancer therapy prior to a DFS event will be censored on 
the date of the last adequate assessment prior to start of subsequent 
anticancer therapy 
Supplementary 2 
Rationale: Evaluation of the hypothetical isolated effect with the study 
intervention while relying on DFS as assessed by IRC. The 
corresponding test will be alpha-controlled if main analysis test confirms 
a significant treatment arm difference for DFS (see also Section 9.4.4). 
Supplementary Analysis: Estimand as defined for main analysis, 
except for the following changes: 
Endpoint: 
DFS as assessed by IRC.  
Intercurrent Event Strategy: 
Use the hypothetical strategy for the intercurrent event ‘Start of 
subsequent anticancer therapy’, i.e. participants who started 
subsequent anticancer therapy prior to a DFS event will be censored on 
the date of the last adequate assessment prior to start of subsequent 
anticancer therapy  
Supplementary 3 
Rationale: Evaluation of the time to local relapse and time to distant 
metastases as subtypes events for of DFS endpoint while considering 
the competing risk of death. 
Supplementary Analysis: Estimand as defined for main analysis, 
except for the following changes: 
Population-Level Summary: 
Cumulative incidence of both local relapse and distant metastasis over 
time between the two study intervention groups will be compared in 
terms of the cause-specific hazard taking the competing risk of death 
prior relapse into account, including confidence interval, estimated by 
means of a cause-specific proportional hazards model (multistage 
approach). Stacked cumulative incidence functions by arm and cause 
based on a proportional hazards model on the cause-specific hazards 
will be plotted. 
Ties will be handled by replacing the proportional hazards model by the 
discrete logistic model. 
Further analyses (e.g. subgroup analyses) will be specified in the 
Integrated Analysis Plan. 
Supplementary 4 
Rationale: Evaluate treatment effect when adjusting for selected 
baseline covariates 
Supplementary Analysis: Estimand as defined for main analysis, 
except for the following change: 
Population-Level Summary: 
Multivariable Cox regression analysis will be carried out to adjust the 
treatment effect for relevant baseline factors of potential prognostic 
impact. 
The Cox's Proportional Hazard model is defined as: h(t) = h(0;t) 
exp(Xb), where h(0;t) defines the baseline hazard function and X 
defines the vector of explanatory variables and b the unknown vector of 
regression parameters. The hazard ratios of all selected explanatory 
variables (note: source should be the clinical database, and not IWRS) 
and of the treatment effect will be reported including 2-sided 95% 
confidence intervals. The following baseline variables will be candidates 
for covariates to be included in the model, in addition to the 
randomization strata and the treatment effect: 
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Estimand 
 
Reference 
#  
Category 
Statistical Analysis 
Further exploratory efficacy estimands will be specified in the Integrated 
Analysis Plan finalized before database lock. 
eCRF=electronic case report form, DFS=disease-free survival, ECOG PS=Eastern Cooperative Oncology Group 
Performance Status, EORTC=European Organization for Research and Treatment of Cancer, EQ=EuroQOL, 
HRQOL=health-related quality of life, IRC=Independent Review Committee, ITT=intention-to-treat, IWRS=interactive 
web response system, MMRM=mixed effect model for repeated measures, OS=overall survival, QOL=quality of life, 
RT=radiotherapy, VAS=visual analog scale. 
9.4.2 
Safety Analyses  
All safety analyses will be performed on the Safety Analysis set. Analyses will consider 
participants as actually treated, i.e. received at least one dose of xevinapant vs. received no dose 
of xevinapant. 
Safety endpoints include AEs, clinical laboratory assessments, vital signs, ECG parameters, and 
ECOG PS. Table 20 provides more details on safety analyses. 
Table 20 
Statistical Analysis Methods for Safety Endpoints  
Estimand Ref # 
Statistical Analysis Methods 
4 - Safety 
Safety will be analyzed on the Safety (SAF) population and will be based on all safety 
analysis reporting outcomes like AEs, AESIs and laboratory tests outcomes. 
The safety endpoints will be tabulated using descriptive statistics. Safety will also be 
tabulated by subgroups. 
The incidence of AEs which includes AESIs, regardless of attribution, will be 
summarized by Preferred Term and System Organ Class for each treatment arm, and 
described in terms of severity according to CTCAE v5 grades and relationship to 
treatment. 
Summary and analysis of AEs will be performed based on the 3-tier approach 
(Crowe 2009). 
Further details will be provided in the Integrated Analysis Plan. 
AE=adverse event, AESI=adverse events of special interest, CTCAE=Common Terminology Criteria for Adverse 
Events. 
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9.4.3 
Other Analyses  
Details on the PK, pharmacogenomics, and biomarker exploratory analyses will be in the 
Integrated Analysis Plan that will be finalized before database lock. 
Pharmacokinetic concentrations of xevinapant and metabolite D-1143-MET1 (in plasma) will be 
listed by visit/timepoint. In addition, PK data from this study will be pooled with data from other 
xevinapant studies, as appropriate, for further analysis via modeling and simulation e.g. population 
PK and exposure-response analyses for efficacy and safety; the details of which will be provided 
in a separate analysis plan to be finalized before database lock. Integrated PK analyses across 
studies, will be presented separately from the main clinical study report. 
9.4.4 
Sequence of Analyses  
Regular external DMC safety review meetings are planned after 12 participants have been 
randomized, treated, and followed up until the end of the combination therapy period and will be 
held every 4 months during recruitment thereafter and twice a year after recruitment has been 
completed if not otherwise requested earlier by the Sponsor or the external DMC. The external 
DMC will also take into consideration available PK data when assessing safety. The planned 
efficacy and futility analyses are shown in Table 21 and corresponding operating characteristics in 
Table 22. 
Table 21 
Planned Efficacy Analyses and Expected Timing  
Analysis 
Events (IF) 
Expected Montha 
After FPI 
Requirements for Confirmatory Test 
DFS PA 
409 (100%) 
50 
𝐻0
𝐷𝐹𝑆 tested in ‘DFS supplementary 2’ analysis only if it can 
be rejected in main analysis 
OS IA1 
344b (69%) 
50 
𝐻0
𝑂𝑆 only tested, if 𝐻0
𝐷𝐹𝑆 can be rejected in ‘DFS 
supplementary 2’ analysis at DFS PA 
OS IA2 
434 (88%) 
66 
𝐻0
𝑂𝑆 only tested, if 𝐻0
𝐷𝐹𝑆 can be rejected in ‘DFS 
supplementary 2’ analysis, but not 𝐻0
𝑂𝑆 at OS IA1 
OS PA 
495c (100%) 
88c 
𝐻0
𝑂𝑆 only tested only if 𝐻0
𝐷𝐹𝑆 can be rejected in ‘DFS 
supplementary 2’ analysis, but not 𝐻0
𝑂𝑆 at OS IA1 or OS IA2 
DFS=disease-free survival, OS=overall survival, IF=information fraction, IA=interim analysis, PA=primary analysis, 
FPI=date of first participant randomized. 
a 
Projections based on assumptions as per Section 9.2. 
b 
OS IA1 is conducted on same data set (and data cut-off date) as DFS PA. 
c 
OS PA is conducted at the earlier of reaching the planned number of events or end of study (Section 4.4). 
As shown in Figure 6, a fixed-sequence strategy is used to test first the null hypothesis 𝐻0
𝐷𝐹𝑆 
(Section 9.1.1) at 1-sided alpha of 2.5% while planning for a total number of 409 DFS events as 
assessed by Investigator in the DFS main analysis, which uses Investigator assessment and the 
treatment-policy strategy for the intercurrent event ‘Start of subsequent anticancer therapy’. If and 
only if 𝐻0
𝐷𝐹𝑆 can be rejected in the main analysis, the full alpha is reallocated to test 
𝐻0
𝐷𝐹𝑆 according to ‘DFS supplementary 2’ analysis as specified in Table 19 on the same data set, 
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which uses the IRC assessment and hypothetical strategy for the intercurrent event ‘Start of 
subsequent anticancer therapy’ (i.e. censoring on the date of the last adequate assessment prior to 
start of subsequent anticancer therapy). If and only if that second test rejects 𝐻0
𝐷𝐹𝑆, the null 
hypothesis 𝐻0
𝑂𝑆 (Section 9.1) is confirmatory tested in a group-sequential design with interim 
analyses as planned in Table 21, which uses alpha-spending according to Lan-DeMets with 
O’Brian-Fleming-like boundaries planning for a total number of 495 OS events at primary analysis. 
That procedure achieves a strong control of the FWER at 2.5% one-sided according to Glimm 
(2010). Table 22 shows the operating characteristics and decision boundaries for the confirmatory 
interim and primary analyses as planned. 
Figure 6 
Fixed-Sequence Strategy to Control FWER at 2.5% 1-Sided, where the 
Arrows Indicate the Alpha Reallocation Applied if the Originating Test 
Rejects its Null Hypothesis Otherwise Confirmatory Testing is 
Discontinued  
 
DFS=disease-free survival, FWER=family-wise error rate, IRC=Independent Review Committee, OS=overall survival. 
Thus, the hierarchical (alpha-controlled) testing strategy is as follows: 
• Primary testing: DFS as assessed by Investigator (DFS Main Analysis according to Table 19) 
• Secondary testing: DFS as assessed by IRC (DFS Supplementary Analysis 2 according to 
Table 19) 
• Tertiary testing: OS (Main Analysis according to Table 19) 
𝜶=  𝟐. 𝟓% 
DFS by Investigator 
(DFS Main 
Analysis) 
DFS by IRC 
(DFS Supplementary 
2 Analysis) 
OS  
(Main Analysis) 
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DFS primary analysis is event driven. The first OS interim analysis will be combined by using 
data from the same data cut-off date when the planned number of DFS events (Table 21) is reached 
for DFS PA. In case 𝐻0
𝐷𝐹𝑆 is rejected at DFS PA and alpha can be reallocated to test 𝐻0
𝑂𝑆 without 
stopping at OS IA1, the second OS interim analysis will be conducted when the planned number 
of OS events (Table 21) is reached. The primary OS analysis is latest conducted (if 𝐻0
𝑂𝑆 could not 
be rejected before and study did not stop for futility on OS) on all data collected until the end of 
the study with all OS events collected even if the planned 495 OS events are not reached (but the 
total of the so far not used alpha will be considered for calculation of the efficacy boundaries at 
that stage to control FWER at 2.5%). Since the observed number of events at interim analyses may 
not be exactly equal to the planned number of events, the efficacy boundaries will be updated 
based on the actual number of observed events using if applicable the prespecified alpha-spending 
functions to maintain the control of the FWER. The final analysis will be conducted on all data 
collected until the end of study. 
Pooled and blinded efficacy data will be used for event projections to allow for in-time preparation 
of the efficacy analyses according to the planned event numbers in Table 21. The cut-off date will 
be the date on which approximately the planned number of events are expected in the FAS based 
on the latest event projection, if the approximate event number can be confirmed by a blinded data 
review meeting before (partially) locking the data base. 
Continuous cleaning is implemented throughout the conduct of the clinical study for all participant 
data collected, though an extra cleaning period is foreseen according to the external DMC Charter 
and other relevant documents for each external DMC review as well as all analyses listed in 
Table 21. In particular, the high-quality expectation for regulatory filing is provided on all 
dimensions of collected participant data at all prespecified efficacy interim analyses. 
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carcinoma of the head and neck unsuitable to receive cisplatin-based therapy. Front Oncol 
2020;9:1522.  
Radiologists. The timely delivery of radical radiotherapy: guidelines for the management of 
unscheduled treatment interruptions. Fourth edition. Clin Oncol (R Coll Radiol) 2019;1-37.  
 
  
Schwartz LH, Litiere S, de Vries E, et al. RECIST 1.1-Update and clarification: From the RECIST 
committee. Eur J Cancer 2016;62:132-7.  
Serova M, Raballand AT, Albert S, et al. Effects of Debio 1143, a novel oral IAP inhibitor, in 
monotherapy and in combination with platinum drugs in human SCCHN tumor specimens. In: 
Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 
Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19):Abstract.  
Sun XS, Tao Y, Le Tourneau C, et al. Debio 1143 and high-dose cisplatin chemoradiotherapy in 
high-risk locoregionally advanced squamous cell carcinoma of the head and neck: a double-blind, 
multicentre, randomised, phase 2 study. Lancet Oncol 2020;21:1173-87.  
Tamm I, Kornblau SM, Segall H, et al. Expression and prognostic significance of IAP-family 
genes in human cancers and myeloid leukemias. Clin Cancer Res 2000;6(5):1796-803.  
Tao Z, McCall NS, Wiedemann N, et al. SMAC Mimetic Debio 1143 and Ablative Radiation 
Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer. Clin Cancer Res 
2019;25(3):1113-1124.  
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The R Project for Statistical Computing. The R Foundation. https://www.r-project.org/. Accessed 
October 2023. 
Tolcher AW, Bendell JC, Papadopoulos KP, et al. A Phase I Dose-Escalation Study Evaluating 
the Safety Tolerability and Pharmacokinetics of CUDC-427, a Potent, Oral, Monovalent IAP 
Antagonist, in Patients with Refractory Solid Tumors. Clin Cancer Res 2016;22(18):4567-73.  
Vermorken JB, Kapteijn TS, Hart AAM, et al Ototoxicity of cis-diamminedichloroplatinum (II): 
Influence of dose, schedule and mode of administration. Eur J Cancer Clin Oncol 1983;19 (1):53-58  
Ward GA, Lewis EJ, Ahn JS, et al. ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 
and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor 
Growth. Mol Cancer Ther 2018;17(7):Epub.  
 
  
WHO Guidelines for the Pharmacological and Radiotherapeutic management of cancer pain in 
adults and adolescents, 2018.  
 
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11 
Appendices  
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Appendix 1 
Abbreviations  
18F-FDG-PET 
2-deoxy-2- [fluorine-18] fluoro-D-glucose positron emission tomography 
ADR 
adverse drug reaction 
AESI 
adverse events of special interest 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
Bpm 
beats per minute 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CRT 
chemoradiotherapy 
CT 
computed tomography 
 
 
CTV 
clinical target volume 
CxDx 
cycle x day x 
DDI 
drug-drug interaction 
DFS 
disease-free survival 
DILI 
drug-induced liver injury 
DMC 
Data Monitoring Committee 
ECE 
extra-capsular extension 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic Case Report Form 
EORTC QLQ-C30 
European Organization for research and Treatment of Cancer Quality of 
Life Core Questionnaire 
EORTC QLQ-
HN35 
European Organization for research and Treatment of Cancer Quality of 
Life Head and Neck Module 
EOS 
end of study 
EOT 
end of treatment 
EQ-5D-5L 
EuroQOL 5 Dimension 5 Level Health-Related Quality of Life Measure 
ESMO 
European Society for Medical Oncology 
FAS 
full analysis set 
FFPE 
formalin-fixed paraffin-embedded 
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FPI 
date of first participant randomized 
FU 
follow-up 
FWER 
family-wise error rate 
GCP 
good clinical practice 
GI 
gastroinstestinal 
GTV 
gross tumor volume 
HBsAG 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotrophin 
HCP 
healthcare practitioner 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPV 
human papillomavirus 
HR 
hazard ratio 
HRQoL/HRQL 
health-related quality of life 
HRU 
health resource utilization 
IA 
interim analysis 
IAP 
inhibitor of apoptosis proteins 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICRU 
International Commission on Radiation Units 
IEC 
Independent Ethics Committee 
IF 
information fraction 
IGRT 
image guided radiation therapy 
IHC 
immunohistochemistry 
IMP 
Investigational Medicinal Product 
IMRT 
intensity modulated radiation therapy 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITT 
intention-to-treat 
IV 
intravenous 
IWRS 
interactive web response system 
LA SCCHN 
locally advanced squamous cell carcinoma of the head and neck 
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LRC 
locoregional control 
MMRM 
mixed effect model for repeated measures  
MoA 
mechanism of action 
MRI 
magnetic resonance imaging 
NCCN 
The National Comprehensive Cancer Network 
NIMP 
noninvestigational medicinal product 
OPC 
oropharynx 
OS 
overall survival 
PA 
primary analysis 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
progression free survival 
PGIC 
Patient Global Impression of Change  
PGIS 
Patient Global Impression of Severity Scale 
PK 
pharmacokinetics 
PRO 
patient-reported outcomes 
PRO CTCAE 
Patient-Reported Outcomes Version of the Common Terminology 
Criteria for Adverse Events 
PT 
preferred term 
PTV 
planning target volumes 
PTVeval 
planned target volume evaluation 
QA 
Quality Assurance 
QoL 
quality of life 
QTcF 
QTc using Fridericia’s formula 
QTL 
quality tolerance limits 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RT 
radiotherapy 
SAD 
short axis diameter 
SAE 
serious adverse event 
SAF 
safety analysis set 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus-2 
SCCHN 
squamous cell carcinoma of the head and neck 
SIB 
simultaneous integrated boost 
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SJS 
Stevens-Johnson syndrome 
SoA 
schedule of activities 
SoC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse events 
TEN 
toxic epidermal necrolysis 
ULN 
upper limit of normal 
VAS 
visual analog scale 
VMAT 
volumetric modulated arc therapy 
WOCBP 
women of childbearing potential 
wk(s) 
week(s) 
 
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Appendix 2 
Clinical Laboratory Tests  
The protocol-required clinical laboratory assessments are in the following table: 
Laboratory 
Assessments 
Parameters 
Blood 
Hematology 
Platelet count 
Hemoglobin 
Hematocrit 
Erythrocytes (RBC) 
Mean corpuscular 
volume (MCV) 
Mean corpuscular 
hemoglobin (MCH) 
White blood cell count 
(absolute/%) with differential 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
Blood 
Biochemistry1  
(full panel) 
Blood urea nitrogen/ 
urea 
Creatinine 
Glucose 
C reactive protein 
Uric acid 
Potassium 
Sodium 
Calcium 
Magnesium 
Amylase 
Albumin 
Lipase 
Aspartate 
aminotransferase1 
Alanine 
aminotransferase1 
Alkaline 
phosphatase2 
Phosphate 
Bilirubin (total) (if > ULN: direct 
bilirubin as well) 
Protein (total) 
eGFR (calculated) 
 
Blood 
Biochemistry1 
(minimum 
panel) 
Blood urea nitrogen / 
urea 
Creatinine 
Amylase 
Potassium 
Sodium 
Magnesium 
Lipase 
Aspartate 
aminotransferase1 
Alanine 
aminotransferase1 
Alkaline 
phosphatase2 
Bilirubin (total) (if > ULN: direct 
bilirubin as well) 
 
Notes: 
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1 and Table 8. 
2 If alkaline phosphatase is elevated, consider measuring the alkaline phosphatase isoenzymes. 
Routine 
Urinalysis 
• Specific gravity  
• pH, glucose, protein, blood, ketones, leukocytes by dipstick 
• Microscopic examination (only at Screening and End of Treatment, at other visits only if blood 
or protein is abnormal).  
Coagulation 
• Prothrombin Intl. Normalized Ratio, if applicable (e.g. under oral anticoagulation medication) 
• Activated partial thromboplastin time 
• Fibrinogen 
Other 
Screening 
Tests 
• Follicle Stimulating Hormone (for females, as needed, if not WOCBP). 
• Serum hCG pregnancy test (as needed for a WOCBP) during screening, local urine test 
thereafter. 
• HBsAg and HBcAb (see Appendix 12 for specific requirements in Japan). 
• HCV-antibody and HCV-RNA by PCR. 
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Laboratory 
Assessments 
Parameters 
• HIV 1/2 antibodies. 
• HPV status by p16 IHC 
• SARS-CoV-2 (RNA by PCR and/or antigen test) (see Section 5.2 when test is applicable) 
All study-required laboratory assessments will be performed by a central laboratory, except for the laboratory tests 
to confirm eligibility for treatment on CxD1 which may be obtained locally (eGFR, platelet counts, absolute 
neutrophil count, hemoglobin, alanine transferase, aspartate aminotransferase, urine pregnancy test [pregnancy 
test at C1D1, C2D1, C3D1, C4D1, C5D1, C6D1 and EOT]). See Section 8.2.4 for further instructions. 
 
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Appendix 3 
Conduct of the Study during the COVID-19 Pandemic  
Benefit/Risk Assessment of the Conduct of the Study During the COVID-19 Pandemic 
Efficacy results from the 36-month analysis of Debio 1143-201 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 54% in the xevinapant group compared to the placebo group (hazard ratio 0.46 
[95% CI: 0.19;1.13], p=0.0893). 
Xevinapant + CRT treatments also demonstrated a 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 67% in 
the risk of disease progression or death in the xevinapant group compared to the placebo group 
(hazard ratio 0.33 [95% CI: 0.17;0.67], p=0.0019). 
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: 50;78) 
in the xevinapant arm versus 51% (95% CI: 35;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=0.0271. 
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 
mg/day were safely 
combined with either chemotherapy, RT or both. In Study Debio 1143-201, xevinapant was 
administered to participants with LA SCCHN in combination with cisplatin and standard RT. An 
increased risk of nausea, mucosal inflammation, dysphagia, weight decrease, radiation skin injury, 
tinnitus, hyperlipasemia, elevation of transaminase and Grade 3 anemia was observed versus 
placebo. Nevertheless, the safety profile of xevinapant used in combination with CRT remained 
acceptable and manageable. 
The COVID-19 pandemic globally affected the society in many aspects, including the conduct of 
clinical studies. While cancer patients are a subpopulation at increased risk during the pandemic, 
they are also a patient population in urgent need of receiving treatment for their disease. Therefore, 
during the COVID-19 pandemic, the decision to start cancer treatment is very individual and relies 
on a thorough benefit/risk analysis per patient by the treating physician. 
Recommendations for Mitigation Measures During the COVID-19 Pandemic 
• Considerations for participants’ eligibility 
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The safety of the clinical study participants is of primary importance. The individual benefit-risk 
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. 
Furthermore, special attention should be paid to those participants with additional risk factors for 
more serious COVID-19. 
• Recommendations for the initiation of study intervention 
In the context of the study protocol exclusion criteria #7 “Other infections (viral [including 
COVID-19] and/or bacterial and/or mycotic) requiring systemic treatment”, a COVID-19 
diagnostic test (PCR or antigen test) is mandatory during Screening, except for participants who 
have completed vaccination against SARS-CoV-2 or who have recovered from confirmed 
COVID-19 at Screening, as per local regulations. The result of this diagnostic test should be 
available before randomization. If the test is positive, irrespective of the absence or presence of 
symptoms, the initiation of the study intervention should be postponed until any existing symptoms 
have resolved and a follow-up test (PCR or antigen test) is negative. 
If initiation of treatment is postponed, study intervention should not be started before a negative 
COVID-19 test result. Additionally, in case of symptoms, study intervention 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 confirmed COVID-19 cases should be reported as 
an AE even if they are asymptomatic. 
• Recommended study procedures in case of COVID-19 pandemic in study site area 
Recommendations for the management of participants enrolled in the study during the COVID-19 
pandemic are listed below. There might be specific national legislation and guidance in place, 
which can be considered to complement these recommendations, or may take priority over these 
recommendations. 
In case the hospital facility cannot ensure the safety of the study participants during the visits 
despite of all efforts made, the following procedures must be considered: 
• Certain study assessments, especially those related to safety, such as ECGs and blood 
monitoring (Section 8.2) 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 routinely perform such tests, if this can be done within local rules on social distancing. 
However, all procedures related to the primary endpoint (clinical and radiological 
evaluations as listed in Section 8.1) should be performed at the study site. 
• This decision will be at the Investigator’s discretion, based on an assessment of potential risk 
of SARS-CoV-2 infection between a visit to the study site versus a visit to another institution. 
• Additionally, the above exception should also be considered in case of operational limitations 
at the site e.g. overburden of the site laboratories due to management of COVID-19 patients. 
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• Assessments done in other institutions will be accepted for study purposes if the data generated 
by these institutions are included in the participants medical records to allow for study data 
entry and monitoring. 
• To minimize the likelihood that the participant might run out of study intervention in case 
she/he has to skip visits due to the risk of COVID-19, the study intervention may be shipped 
from sites to the participant’s residence according to the site’s internal procedures, local 
laws/regulations for privacy data protection, and according to the product specifications. 
The sites must inform the CRO and the Sponsor immediately about the implementation of any of 
the above adaptations or measures. 
In case a participant becomes infected with SARS-CoV-2 during the treatment period, the 
Investigator must consider any study treatment modification in the best interest of the participant 
and in accordance with the protocol (Section 6.5.1.2; Table 8). This includes an evaluation of 
potential DDI if the use of concomitant medications is necessary to manage COVID-19 
(Section 6.8). 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 eCRF. 
Note: in case of study intervention discontinuation, it is 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 exceptional and justified cases and only if strictly necessary, rSDV can take place. For Germany 
specific: In case of rSDV implementation, 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 
The above 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 measures will be captured in the Trial Master File 
for the study and will be described in the clinical study report. 
These rules will not apply once the COVID-19 pandemic will be declared to have ended in the 
applicable country. 
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Appendix 4 
Contraception and Barrier Requirements  
Definitions: 
WOCBP: 
A woman is of childbearing potential (fertile) following menarche and until becoming 
postmenopausal unless permanently sterile, as specified below. 
If fertility is unclear (e.g. amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, consider additional evaluation. 
Postmenopause: 
Postmenopause is defined as no menses for 12 months without an alternative medical cause. 
• A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state 
in a female not using hormonal contraception or HRT. However, in the absence of 12 months 
of amenorrhea, confirmation with more than 1 FSH measurement (> 40 IU/L or 40 mIU/mL) is 
required. 
• A female on HRT and whose menopausal status are in doubt will be required to use one of the 
nonestrogen hormonal highly effective contraception methods if she wishes to continue her 
HRT during the study. Otherwise, she must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
Permanent Sterilization: 
For this study, permanent sterilization includes: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Documentation can come from the site personnel’s review of the individual’s medical records, 
medical examination, or medical history interview. 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g. Mullerian agenesis, androgen insensitivity), Investigator discretion applies to determine study 
entry. 
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Contraception Guidance: 
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methods That Have Low User Dependency 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
• IUD 
• IUS 
• Bilateral tubal occlusion 
• Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided the partner is the sole sexual partner of the 
WOCBP and the absence of sperm has been confirmed. Otherwise, use an additional highly effective method of 
contraception. The spermatogenesis cycle is approximately 90 days. 
Documentation can come from the site personnel’s review of the individual’s medical records, medical 
examination, or medical history interview. 
Highly Effective Methods That Are User Dependent 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
Oral 
Intravaginal 
Transdermal 
Injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulation 
Oral 
Injectable 
• Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire period 
of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the study and the preferred and usual lifestyle of the participant. 
Barrier Methods (to be used in addition to a highly effective method) 
• Male or female condom with or without spermicide 
• Cap, diaphragm, or sponge with spermicide 
Notes: 
Contraceptive use by men or women is consistent with local regulations on the use of contraceptive methods for 
clinical study participants, except for Japan (for details see Appendix 12). 
Highly effective methods are those with a failure rate of <1% per year when used consistently and correctly. 
Typical use failure rates differ from those when used consistently and correctly. 
Hormonal contraception may be susceptible to interaction with the study intervention(s), which may reduce the 
efficacy of the contraceptive method. As such, 1) barrier methods (male or female condom with or without 
spermicide; cap, diaphragm, or sponge with spermicide) in addition to hormonal contraception or 2) a non-
hormonal intrauterine device must be used. If locally required, in accordance with CTFG guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM are not acceptable methods of contraception for this study. Male condom and female 
condom cannot be used together (due to risk of failure from friction). 
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Appendix 6 
Study Governance  
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. This information is required 
during the study and for 1 year after completion of the study. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative (where allowed by local laws and regulations) and 
answer all questions on the study. 
• Participants will be informed that their participation is voluntary. 
• Participants or their legally authorized representative (where allowed by local laws and 
regulations) will be required to sign a statement of informed consent that meets the requirements 
of 21 CFR 50; the Japanese ministerial ordinance on GCP; local regulations; ICH guidelines; 
HIPAA requirements, where applicable; and the IRB/IEC or study center. 
• The medical record 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. The 
authorized person obtaining the informed consent will also sign the ICF. 
• If the ICF is updated during their participation in the study, participants will be re-consented to 
the most current, approved version. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. 
The original signed and dated consent will remain at the Investigator’s site and must be safely 
archived so that it can be retrieved at any time for monitoring, auditing and inspection purposes. 
• Participants who are rescreened are required to sign a new ICF. 
Data Protection 
• The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. Any participant records or datasets that are transferred to the Sponsor will contain the 
identifier only; participant names or any identifiable information will not be transferred. 
• The Sponsor will inform participants that their personal study-related data will be used per local 
data protection and privacy laws. The level of disclosure will also be explained to the participant 
and pregnant partners (if applicable), who will be required to give consent for their data to be 
used, as specified in the informed consent. 
• The participant will be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by appropriate 
IRB/IEC members, and by regulatory authority inspectors. All such persons will strictly 
maintain participants’ confidentiality. 
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• The Investigator and Sponsor will comply with all applicable regulations to protect personal 
data. If a data security breach occurs at the site, the Investigator will inform the Sponsor within 
24 hours after becoming aware of the event. The Sponsor will manage the breach in accordance 
with their processes, including where applicable regulatory authority and/or IRB/EC 
notification. 
Study Administrative 
Site and country selection will be based on historic enrollment data and the results of a feasibility 
assessment. It is anticipated to be conducted in in the US, Canada, Europe, Latin America, and 
Asia-Pacific. Sites will include clinical centers and academic centers, mostly in an outpatient 
setting. 
The Coordinating Investigator listed on the title page represents all Investigators for decisions and 
discussions on this study, per ICH GCP. The Coordinating Investigator will provide expert medical 
input and advice on the study design and execution and is responsible for the review and signoff 
of the clinical study report. 
Several activities are outsourced to third-party service providers. These providers and activities 
include, but are not limited to a CRO, central laboratory, ePRO, IRT, imaging, and CDMO. 
Drug supply and distribution are handled via CDMO including regional depots. 
Details of structures and associated procedures will be defined in a separate Operations Manual. 
External Data Monitoring Committee 
An external DMC will be formed in this study before the randomization of the first participant and 
will assess the safety, PK and efficacy during the study (see Section 8.2.5 for details). The external 
DMC will consist of expert members who are independent of the Sponsor. The members will be 
appointed by the Sponsor based on their expertise in clinical studies, biostatistics, clinical 
pharmacology, and oncology. Members will not be investigators in the study, nor will they have 
any conflict of interest with the Sponsor. 
The responsibilities of the external DMC include: 
• Performing a safety review after 12 participants have been randomized, treated, and followed 
up until the end of the combination therapy period and hereafter every 4 months during 
recruitment and twice a year after recruitment has been completed if not otherwise requested 
earlier by the Sponsor or the external DMC. 
• Minimizing the exposure of participants to an unsafe therapy or dose. 
• Making recommendations for changes in study processes where appropriate. 
• Advising on the need for dose adjustments because of safety issues. 
• Endorsing continuation of the study. 
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• Review available PK exposure and safety data in participants ineligible for high-dose 
cisplatin, including participants with moderate renal impairment. 
At any time during the study when the external DMC recommends major changes, these 
recommendations will be presented to the SSC. Further details on the objectives, roles and 
responsibilities, operational procedures, data outputs and data review are described in a separate 
external DMC Charter. 
RT-QA Review Center 
One or more RT-QA Review Centers will be identified. The responsibilities of the RT-QA Review 
Center can include: 
• Reviewing and approving IMRT plan(s) before starting the first fraction administration to 
ensure IMRT requirements compliance 
• Approving the dosimetry planning before IMRT start 
• Confirming IMRT treatment delivery as per the approved planning and evaluate any 
critical/major deviations from the submitted plan 
A RT-QA 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. 
Independent Review Committee 
The IRC will perform a blinded central review of histopathology and radiological imaging of all 
participants. Details of structures and associated procedures will be defined in a separate Imaging 
Charter, Independent Review Charter and histopathology guidelines. 
Study Steering Committee 
The SSC is a multidisciplinary group of Investigators that, collectively, have experience/expertise 
in the management of patients with condition(s) relevant to study and anticipated adverse effects, 
and in the conduct and monitoring of randomized clinical studies. The SSC will also include 
representatives of the Sponsor. The SSC will ensure transparent management of the study 
according to the protocol as initially written and through decisions made based on the external 
DMC recommendations. Details on the membership and responsibilities of the SSC are described 
in the SSC Charter. 
In particular, the SSC 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 external DMC and/or other study committees and 
suggesting appropriate action to the Sponsor. 
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• 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 SSC are described in the SSC Charter. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and the following: 
Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and CIOMS International Ethical Guidelines 
Applicable ICH GCP Guidelines 
For studies with Japanese sites, the Japanese ministerial ordinance on GCP 
Applicable laws and regulations 
• The protocol, protocol amendments (if applicable), ICF, Investigator Brochure, and other 
relevant documents (e.g. advertisements) will be submitted to an IRB/IEC for review and 
approve before the study is initiated. 
• For studies with Japanese sites, the Sponsor initiates the study at a site after obtaining written 
approval from the Head of the study site, based on favorable opinion/approval from the 
concerned IRB. 
• Any protocol amendments (i.e. changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary to 
eliminate an immediate hazard to study participants. When applicable, amendments will be 
submitted to the appropriate Health Authorities. 
• The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site. 
Emergency Medical Support 
• The Sponsor or designee will provide Emergency Medical Support cards to participants for use 
during the study. These provide the means for participants to identify themselves as 
participating in a clinical study. Also, these give health care providers access to any information 
about this participation that may be needed to determine the course of medical treatment for the 
participant. The information on the Emergency Medical Support card may include the process 
for emergency unblinding (if applicable). 
• The first point of contact for all emergencies will be the clinical study Investigator caring for 
the participant. Consequently, the Investigator agrees to provide his or her emergency contact 
information on the card. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action (e.g. unblinding) will follow the standard process 
established for Investigators. 
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When the Investigator is not available, the Sponsor provides the appropriate means to contact a 
Sponsor (or designee) physician. This includes provision of a 24-hour contact number at a call 
center, whereby the health care providers will be given access to the appropriate Sponsor (or 
designee) physician to assist with the medical emergency and to provide support for the potential 
unblinding of the participant concerned. 
Clinical Study Insurance and Compensation to Participants 
The Sponsor is entirely responsible for AEs that are associated with this study and cause damage 
to the health of the participants, except for AEs caused by an intentional and/or significant 
deviation on the part of the Investigator, the study site, and/or the participant. The Sponsor takes 
out insurance to fulfill the responsibility. 
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions will meet good local standards, as applicable. 
Clinical Study Report 
After study completion, the Sponsor will write a clinical study report in consultation with the 
Coordinating Investigator. 
Publication 
• The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows Merck to protect proprietary information and to provide comments. 
• The Sponsor will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice, the Sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. 
• Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
• Following the primary analysis for DFS, a clinical study report will be written by the Sponsor 
in consultation with the Coordinating Investigator following the guidance in ICH Topic E3 and 
will be submitted in accordance with local regulations. Further analyses for OS will be reported 
in a CSR addendum, if applicable. 
• Posting of data on ClinicalTrials.gov, EudraCT, and all other required registries is planned and 
will occur 12 months after the last clinic visit of the final study participant or another appropriate 
date to meet applicable requirements. 
• No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement. 
Data Quality Assurance 
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• All participant study data will be recorded on printed or electronic eCRFs or transmitted to the 
Sponsor or designee electronically (e.g. laboratory data). The Investigator is responsible for 
verifying that data entries are complete, accurate, legible, and timely by physically or 
electronically signing the eCRF. Details for managing eCRFs are in the Operations Manual. 
• For PRO data (e.g. QOL and pain assessments), ePRO will be used. 
• The Investigator will maintain accurate documentation (source data) that supports the 
information in the eCRF. 
• The Investigator will permit study-related monitoring, quality assurance audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to the study file and source 
data. 
• QTLs will be predefined and documented in the Integrated Project Management Plan to help 
support the identification of systematic issues that could potentially impact participant safety 
and/or reliability of study results. These predefined parameters will be monitored during the 
study and important deviations from the QTL thresholds and remedial actions taken will be 
summarized in the clinical study report. 
• Monitoring details describing strategy (e.g. risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are in the Monitoring Plan. 
• The Sponsor or designee is responsible for data management of this study, including quality 
checking of the data and maintaining a validated database. Database lock will occur once quality 
control and quality assurance procedures have been completed. Details will be outlined in Data 
Management documents and procedures. 
• Study Monitors will perform ongoing source data verification to confirm that data in the eCRF 
are accurate, complete, and verifiable; that the safety and rights of participants are being 
protected; and that the study is being conducted per the currently approved protocol and any 
other study agreements, ICH GCP, the Japanese ministerial ordinance on GCP, and all 
applicable regulatory requirements. 
• The Investigator will retain records and documents, including signed ICFs, pertaining to the 
conduct of this study for 15 years after study completion, unless local regulations, institutional 
policies, or the Sponsor requires a longer retention. No records may be destroyed during the 
retention period without the Sponsor’s written approval. No records may be transferred to 
another location or party without the Sponsor’s written notification. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 
• The Investigator will maintain source documents that support the data recorded in the eCRFs. 
• Data recorded on eCRFs that are transcribed from source documents will be consistent with the 
source documents or the discrepancies will be explained. The Investigator may need to request 
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previous medical records or transfer records, depending on the study. Also, current medical 
records will be available. 
• Source documents are stored at the site for the longest possible time permitted by the applicable 
regulations, and/or as per ICH GCP guidelines, whichever is longer. The Investigator or a record 
retainer designated by the Head of the study site ensures that no destruction of medical records 
is performed without the Sponsor’s written approval. 
• Definition of what constitutes source data is found in the Clinical Monitoring Plan. 
Study and Site Start and Closure 
The study start date is when the first participant signs the ICF. 
Study and Site Closure 
The Investigator may initiate site closure at any time, provided there is reasonable cause and 
enough notice is given in advance of the intended closure. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further development of the Sponsor’s compound 
• Sponsor discontinuation of the study due to an unacceptable risk, any relevant toxicity, or 
negative change in the risk/benefit assessment. 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any third-party service providers of 
the reason for termination or suspension, as specified by the applicable regulatory requirements. 
The Investigator will promptly inform the participants and assure appropriate participant therapy 
and/or follow-up. 
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Appendix 7 
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Applied to Adjuvant Studies of Squamous Cell 
Carcinoma of the Head and Neck  
The following text was derived from Eisenhauer (2009) and Schwartz (2016). It has been adapted 
to apply to surgically excised head and neck cancer where no macroscopic residual disease is 
expected at Screening. 
DEFINITIONS 
Relapse in resected SCCHN may be local, regional, or as distant metastasis or a combination of 
these. The term relapse is used below to cover both possibilities, although sites will need to 
differentiate between locoregional relapse “new lesions local” or “new regional nodes” and distant 
metastasis “new lesions distant” on the eCRF. 
Relapse will be evaluated in this study using an approach for relapse adapted from the international 
criteria of the RECIST Committee (Version 1.1). As absence of macroscopic residual disease is 
an inclusion criterion for such studies, participants will not have measurable disease at study entry; 
there will be no target or non-target lesions at baseline, and the only features to be measured will 
be normal lymph nodes, which need only to be measured retrospectively if enlargement is 
suspected. Therefore, many of the usual components of RECIST assessment will not apply in this 
study. 
Lymph nodes: Lymph nodes do merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. Lymph nodes are measured in 
short axis diameter (SAD) which is the longest measurement perpendicular to the longest diameter 
of the node, and only the SAD of lymph nodes will be considered. The SAD of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is 
normally reported in the plane in which the image is obtained (for CT scan this is almost always 
the axial plane; for MRI the plane of acquisition may be axial, sagittal, or coronal). Nodes that 
have a SAD < 10 mm are considered nonpathological and should be reviewed and measured 
retrospectively only if they subsequently become enlarged (≥ 10.0 mm SAD but see relapse criteria 
below). 
IMAGING MODALITIES FOR ASSESSMENT OF RELAPSE 
For all suspected disease relapse that is detected clinically (by endoscopy), but is not visible on 
radiographic imaging, an objective evidence supporting disease relapse must be collected and 
submitted to IRC. Tissue (biopsy) confirmation of disease is required for all local and regional 
suspected relapse of disease unless medically contraindicated. Photographs and reports from 
endoscopy procedure should be collected by the site (if available) and both should be submitted to 
IRC for central review, including those performed during screening. If biopsy has been performed 
during screening to exclude presence of residual disease, upon IRC request biopsy reports may be 
presented to the IRC. Please refer to the Imaging Charter for detailed information. 
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In addition, the most recent pre-surgery diagnostic/staging CT and/or MRI scans done as a part of 
SoC should be submitted to the IRC vendor, if available, as well as any recent pre-surgery or 
baseline PET-CT scan if acquired, to facilitate IRC assessment of any potential macroscopic 
residual disease at baseline. 
• CT, MRI 
CT is the best currently available and reproducible method to measure lesions selected for 
imaging assessment. The same method of assessment and the same technique should be used at 
baseline and during Follow-up. Imaging based evaluation and/or biopsy should always be done 
unless the lesion(s) being followed cannot be imaged but are assessable by clinical examination 
and biopsy. 
• Cytology, histology 
These techniques can be used to differentiate between relapse, nonmalignant lesions and second 
(other) primary tumor. 
• FDG-PET scans 
It is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of relapse in the absence of biopsy. Relapse on the basis of FDG-PET 
imaging can be identified according to the following algorithm: 
a. Earlier negative FDG-PET, with a later positive FDG-PET sign of PD based on a relapse. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is relapse. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly relapse occurring at that site (if so, the date 
of relapse will be the date of the initial abnormal FDG-PET scan). 
Ultrasound, laparoscopy, and bone scan are modalities that are not allowed to be used to assess 
relapse in the current study. Lesions detected using these modalities must be confirmed by 
CT/MRI/PET (However, plain radiography and ultrasound scans may be submitted for biopsy 
localization only). 
RELAPSE CRITERIA 
• New Lesions (non-nodal) 
The appearance of new malignant lesions denotes disease relapse unless known to be 
non-squamous. There are no specific criteria for the identification of new radiographic lesions; 
however, 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. 
Any lesion identified on a follow-up image in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate relapse. If a new lesion is equivocal, for 
example because of its small size, and biopsy is not possible because it is medically 
contraindicated or the medical risk of biopsy is assessed as too high, continued observation and 
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follow-up evaluation will clarify if it represents truly new disease. If the equivocal lesion 
persists on the follow-up scan and has qualitatively/quantitatively increased in size and/or a 
second new lesion has developed, this then definitely reflects relapse. If repeat scans confirm 
there is a new lesion, then relapse should be declared using the date of the initial scan. 
• New nodal lesions 
For diagnosis of relapse, either biopsy confirmation OR, in the absence of biopsy, at least one 
node that is > 10 mm in SAD AND has increased by > 5 mm over baseline, is required. Thus, 
a node that was previously 9 mm in SAD must increase to 14 mm in SAD to be considered 
diagnostic of relapse in the absence of a positive biopsy. This methodology allows for the 
5.0 mm variance in measurement used elsewhere in RECIST. 
Measurements of nodes at baseline and on-study must not be recorded unless they subsequently 
become enlarged beyond 10 mm in SAD: only the SAD will be measured and may be recorded 
retrospectively. A small increase in the size of a single node (for example from 9 mm to 10 mm) 
even if above the size threshold for abnormality, is not automatically considered to be relapse 
since this falls within the limits of measurement error. 
Lymph nodes identified as possible sites of relapse, when they are measured, should always 
have the actual SAD measurement recorded (measured in the same anatomical plane as the 
baseline examination) and compared with that of the same nodes at baseline. Biopsy should be 
performed, if possible, unless it is medically contraindicated or medical risk of biopsy is 
assessed as too high; alternatively continued follow-up is advised until relapse is unequivocal. 
The date of relapse will be the date on which the node first met the 10 mm SAD criterion. 
Nodes that are ‘too small to measure’: While on-study, all nodes that later become enlarged 
(≥ 10.0 mm SAD) should have their actual measurements recorded, even when very small (e.g. 
2 mm). However, sometimes lesions or lymph nodes may be so faint on CT scan at some 
timepoints that the radiologist may not feel confident assigning an exact measure and may 
report them as being ‘too small to measure’. When this occurs, it is important that a value be 
recorded on the eCRF. If it is the opinion of the radiologist that the node was not present at 
Screening, the screening 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. The measurement of these lesions is potentially nonreproducible; therefore, providing 
this default value will prevent false detection of relapse based upon measurement error. 
However, as mentioned above, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm. 
• Bone lesions 
Solitary new bone lesions on bone scan or PET should be confirmed malignant by biopsy if 
possible, unless biopsy is medically contraindicated or medical risk of biopsy is assessed as too 
high: at least confirmation by CT/MRI is required. Since there is no residual disease at 
Screening, new sclerotic bone lesions cannot be considered a treatment healing effect, and 
hence should considered to be new lesions. 
For equivocal findings of relapse (e.g. very small and uncertain new lesions), treatment or 
observation may continue until the next scheduled assessment or until biopsy confirmation. If at 
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the next scheduled assessment relapse is confirmed, the date of relapse should be the earlier date 
when relapse was suspected. 
Further details will be in histopathology guidelines and Imaging Charter provided for this study. 
 
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Appendix 8 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
AE Definition 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether considered related to the 
study intervention or not. 
• An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention. For surgical or diagnostic procedures, the condition/illness leading 
to such a procedure is considered as the AE rather than the procedure itself. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g. ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline and are judged to be more severe than expected for the participant’s 
condition are considered clinically significant in the medical and scientific judgment of the 
Investigator (i.e. not related to progression of underlying disease, but may be leading to study 
intervention discontinuation). See Appendix 12 for specific requirements in India. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an AE or a SAE. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as an AE or a SAE if they fulfill the definition of an AE or 
SAE. 
Events NOT Meeting the AE Definition 
• Unless judged by the Investigator to be more severe than expected for the participant’s 
condition, any clinically significant abnormal laboratory findings, other abnormal safety 
assessments that are associated with the underlying disease, the disease/disorder being studied 
within the expectedness for participant’s condition, as judged by the Investigator. See 
Appendix 12 for specific requirements in India. 
• Medical or surgical procedure (e.g. endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
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• Facsimile transmission (fax to mail) of the paper form or any follow-up information is the 
preferred method for transmission and will be done within 24 hours to the Sponsor or its 
designee. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the form sent by overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the form within 24 hours after becoming aware of the event. 
• Additional documents (e.g. laboratory reports, autopsy report, hospital discharge letter) and 
relevant pages from the eCRF may be required in addition (e.g. medical history, concomitant 
medication). The data provided will be consistent with the information in the eCRF. 
Reporting of AESIs 
• For a nonserious AESI, the site will complete the specific AESI report form and notify the 
Sponsor immediately (within 24 hours), using the same process for reporting SAEs, as 
specified above. 
• For a serious AESI, the site will complete an SAE report form, using the SAE reporting 
process, specified above. 
Reporting of Pregnancies 
• Pregnancy will be reported whether related to the study intervention using the applicable 
paper form. 
• The applicable form will be used to report if an abnormal outcome of the pregnancy occurs 
and the child/fetus sustains an event. 
• Facsimile transmission (fax to mail) of the paper form or any follow-up information is the 
preferred method for transmission and will be done within 24 hours to the Sponsor or its 
designee. 
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Appendix 9 
Recommended Dental/Oral Evaluations  
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: 
o Eliminating potential sources of infection. 
o Performing any dental extractions preferably at least 2 weeks before RT. 
o Treating active dental caries and periodontal disease. 
o Treating oral candidiasis. 
o Educating participants about preventive strategies. 
• Some of the strategies to decrease oral and dental complications include: 
o Decrease dry mouth (e.g. by using salivary substitutes and stimulation). 
o Decrease dental caries (e.g. by using topical fluoride). 
o Decrease dentoalveolar infection (e.g. with frequent evaluations to detect and treat disease 
promptly). 
o Decrease osteoradionecrosis (e.g. by extracting teeth before RT). 
o Decrease trismus of the masticatory muscles (e.g. by using custom mouth-opening devices 
to maintain range of motion). 
o Have participant undergo evaluations during and after treatment to help minimize 
complications. 
• During and after treatment, the goals of dental/oral management include: 
o Managing xerostomia. 
o Preventing trismus. 
o Detecting and treating oral candidiasis. 
• Additional goals after treatment include: 
o Preventing and treating dental caries. 
o Preventing postradiation osteonecrosis. 
o Preventing oral candidiasis. 
Dental/oral evaluation can be performed by the dental clinic team of the site or by an external 
dentist. 
 
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Appendix 12 
Country-Specific Requirements  
With the following additions and exceptions, all country-specific protocol requirements are 
outlined within the protocol. 
Japan 
5.1 Inclusion Criteria No.9, eGFR calculation  
For participants enrolled in Japan, eGFR will be calculated using modified CKD-EPI formula with 
Japanese Coefficient 0.813 based on national CKD guidelines (Horio 2010). Modified CKD-EPI 
formula will be used for assessment of ineligibility to cisplatin as well as for safety assessments. 
See Section 5.1, Inclusion criteria #9 and Table 8. 
5.2 Exclusion Criteria No 6, HBV 
HBsAb will be tested for 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. See Section 5.2 for Exclusion Criteria. 
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. 
Appendix 4 Contraception and Barrier Requirements 
The following highly effective contraception methods are not approved in Japan: 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation: 
o 
Intravaginal 
o 
Transdermal 
o 
Injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulation: 
o 
Injectable 
South Korea 
5.1 Inclusion criteria No 11, Contraception use – specific requirement in bold and 
underlined: 
WOCBP and male participants using a highly effective contraception method, have to continue 
using this method until 12 months after the last dose of radiotherapy:  
 
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The Investigator confirms that each participant agrees to use appropriate contraception and 
barriers, if applicable. The contraception, barrier, and pregnancy testing requirements are below. 
a. A female participant 
• Is not breastfeeding 
• Is not pregnant (i.e. has a negative serum pregnancy test, as required by local regulations, 
within 24 hours before the first dose of study intervention) 
• Is not a WOCBP 
o If a WOCBP, uses a highly effective contraceptive method (i.e. with a failure rate 
of < 1% per year), preferably with low user dependency, as described in 
Appendix 4 for the following time periods: 
1. Before the first dose of the study intervention(s), if using hormonal contraception: 
o Has completed at least one 4-week cycle of an oral contraception pill and 
either had or has begun her menses; OR, 
o Has used a depot contraceptive or extended-cycle oral contraceptive for least 
28 days and has a documented negative pregnancy test using a highly 
sensitive assay. 
2. During the study intervention period 
3. After the study intervention period (i.e. after the last dose of study intervention 
is administered) for at least 12 months, after the last dose of radiotherapy and 
agree not to donate eggs (ova, oocytes) for reproduction during this period. 
4. Female participants using hormonal contraception must also use a barrier 
contraception method (preferably male condom) due to potential risk of 
CYP3A4/5 induction by xevinapant which may reduce hormonal contraception 
efficacy. 
b. A male participant 
Agrees to the following during the study intervention period and for at least 12 months 
after the last dose of radiotherapy 
• Refrains from donating fresh unwashed semen 
PLUS, either 
o Abstains from any activity that allows for exposure to ejaculate 
OR 
Uses a male condom: 
o When having sexual intercourse with a WOCBP, who is not currently pregnant, 
and instructs her to use a highly effective contraceptive method with a failure rate 
of < 1% per year, as described in Appendix 4 since a condom may break or leak. 
o When engaging in any activity that allows for exposure to ejaculate. 
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France 
5.1 Inclusion criteria No 9 - – specific requirement in bold and underlined: 
9 Are unfit to receive high-dose cisplatin by meeting one or more of the following criteria: 
• eGFR < 60 mL/min /1.73 m2 (using the CKD-EPI creatinine formula) 
• History of hearing impairment, defined as Grade ≥ 3 audiometric hearing loss or tinnitus 
Grade ≥ 3. An audiogram is not required if one of the other criteria meets unfitness to 
receive high-dose cisplatin 
• Peripheral neuropathy ≥ Grade 2 
If ≥ 70 years, unfit according to G8 questionnaire (Score ≤ 14) or ineligible for cisplatin 
treatment due to age limit according to national guidelines 
India 
8.3.3 Regulatory Reporting Requirements for Serious Adverse Events 
For SAE reporting specific for India, as per the guidance in NDCTR 2019, chapter VI: The 
Investigator shall report all serious adverse events to the Central Licensing Authority, the sponsor 
or its representative, who has obtained permission from the Central Licensing Authority for 
conduct of clinical trial or bioavailability or bioequivalence study, as the case may be, and the 
Ethics Committee that accorded approval to the study protocol, according to local regulatory 
requirements.  
Appendix 8 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow- up, and Reporting 
All adverse events meeting AE and subsequently SAE definition irrespective of its 
relatedness/causality need to be reported by the Investigator according to local regulatory 
requirements. 
US 
5.1 Inclusion criteria No 9 - – specific requirement in bold and underlined: 
9.  Are unfit to receive high-dose cisplatin by meeting one or more of the following criteria: 
• eGFR < 60 mL/min /1.73 m2 (using the CKD-EPI creatinine formula).  
• History of hearing impairment, defined as Grade ≥ 2 audiometric hearing loss or tinnitus 
Grade 3. An audiogram is not required if one of the other criteria meets unfitness to receive 
high-dose cisplatin. 
• Peripheral neuropathy ≥ Grade 2 
• If ≥ 70 years, unfit according to G8 questionnaire (Score ≤ 14) or ineligible for cisplatin 
treatment due to age limit according to national guidelines. 
 
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Appendix 13 
Protocol Amendment History  
The information for the current amendment is on the title page. 
Protocol Version 5.0 (25 July 2023) 
The main rationale for this protocol amendment is to extend allowed maximum time window 
between surgery and start of treatment from 8 to 10 weeks, and revise exclusion criterion 13 related 
to history of prior malignancies.   
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities 
Added text in bold and removed 
strikethrough text: If biopsy has been 
performed during screening to exclude 
presence of residual disease, upon IRC 
request biopsy reports should be also 
collected and submitted may be 
presented to the IRC. 
 
Adding text “and except for the 
urinalysis dipstick tests on CxD1, which 
will be done locally”. 
Clarification of IRC process. 
 
 
 
 
 
 
To clarify who will perform the dipstick tests.  
5.1 Inclusion Criteria 
To change the allowed window after 
surgery from 4 – 8 weeks into 4 -10 
weeks.  
To implement feedback from investigators 
5.2 Exclusion Criteria 
To update exclusion criterion #13 as 
follows: 
13. 
History of another malignancy 
prior to randomization, with the following 
exceptions:   
• Completely resected nonmelanoma 
cell skin cancer outside the head and 
neck area or completely resected 
stage I breast cancer, or completely 
resected in-situ nonmuscular invasive 
bladder, cervix and/or uterine 
carcinomas, or T1a squamous 
esophageal carcinomas.  
• Prior malignancy treated with curative 
intent and no relapse and no anti-
cancer treatment within the last 3 
years and does not have potential to 
interfere with the safety or efficacy 
assessments of the study. 
To implement feedback from investigators 
6.5.2.2 Treatment 
To update text in line with exclusion 
criterion 13 into and addition of 
recommendation: Initiation of 
radiotherapy must start 4 to 10 weeks 
after surgery on C1D1 of xevinapant / 
placebo. If possible, it is recommended 
to start treatment within 8 weeks from 
surgery. 
To implement feedback from investigators 
8.2.4 Clinical Safety 
Laboratory 
Assessments 
For the urinalysis dipstick tests, except 
for screening and EOT, the following 
was added as a footnote to Table 16: 
To clarify who will perform the dipstick tests.  
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Section # and Name 
Description of Change 
Brief Rationale 
b: 
Dipsticks 
provided 
by 
central 
laboratory; test done locally. In case of 
abnormal result, microscopic evaluation 
at central laboratory. For screening and 
EOT 
visit, 
urinalysis 
(dipstick and 
microscopic evaluation) done at central 
laboratory 
 
 
 
 
 
 
 
 
 
 
Protocol Version 4.0 (10 May 2023) 
The main rationale for this protocol amendment is to integrate the changes from various local 
amendments into a global amendment, revise the inclusion criterion for ECOG PS to 0-2, 
harmonize pregnancy testing to a frequency of every 3 weeks, adjust the definition of endpoint and 
intercurrent event strategy for the secondary objective on HRQOL, recommend dose modifications 
for eGFR as per TrilynX protocol (Study MS202359_0006 – Phase III study xevinapant and CRT 
in unresected LA SCCHN) and to resolve some identified discrepancies in the protocol.  
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 
Objectives and 
Estimands 
 
3 Objectives and 
Estimands   
Adjusted definition of endpoints and 
intercurrent event strategy of the 
objective for HRQOL 
To align with Health Authority 
recommendation received and implemented 
for another study of xevinapant in a similar 
LA SCCHN setting 
1.3 Schedule of 
Activities 
Added text to specify the screening 
window of 28 days until randomization 
For clarity 
1.3 Schedule of 
Activities  
 
Added text to clarify that biopsy reports 
collected during screening, should be 
submitted to IRC 
To facilitate IRC assessment of potential 
macroscopic residual disease at baseline 
Appendix 7- 
Response Evaluation 
Criteria in Solid 
Tumors (RECIST) 
Version 1.1 Applied 
to Adjuvant Studies 
of Squamous Cell 
Carcinoma of the 
Head and Neck 
Added text to clarify that endoscopy 
photographs and reports and biopsy 
reports collected during screening, 
should be submitted to IRC 
1.3 Schedule of 
Activities, Table 1 
Deleted the C3D2 visit  
To resolve discrepancy 
1.3 Schedule of 
Activities, Table 2 
 
In case of premature treatment 
discontinuation: 
To ensure that all participants are evaluated 
by the same schedule and for better clarity 
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Section # and Name 
Description of Change 
Brief Rationale 
Deleted text “CT/MRI scan to be 
performed at least 3 months (±2 wks) 
after ending IMRT”.  
Added revised text “tumor assessments 
to be performed according to original 
schedule (Week 20 for EOT 
assessment)” 
1.3 Schedule of 
Activities, Table 4 
 
Deleted text “The DFS FU period starts 
immediately after EOT visit”. 
Added revised text “while imaging and 
clinical tumor assessments will follow 
original schedule, starting from Month 9" 
8.1.1 Radiological 
Assessment 
Added text Tumor assessments to be 
performed according to original 
schedule regardless of premature 
treatment discontinuations or treatment 
delays 
1.3 Schedule of 
Activities, Table 1 
and Table 2,  
8.2.4 Clinical Safety 
Laboratory 
Assessments,  
Table 16 
Appendix 2 
Addition of Pregnancy testing at C2D1, 
C4D1 and C6D1 
To comply with local regulatory requirements 
for Pregnancy testing the frequency is 
harmonized and to be conducted every 
3 weeks 
 
1.3 Schedule of 
Activities, Table 4 
Text for Survival 
follow up telephonic 
visit added at M39 
visit  
Included Month 39 for telephone 
follow- up 
To ensure consistency across the protocol 
for 3 monthly follow-up for survival status 
1.3 Schedule of 
Activities, Table 6 
Time point for PK 
sampling to be 
clarified  
Column for Dosing of Xevinapant 
removed 
Added time frame for sample collection 
at C4D1, C5D1 and C6D1 
Resolve discrepancy between dosing and 
PK collection timepoints 
4.2-Scientific 
Rationale for Study 
Design 
 
 
5.1-Inclusion Criteria 
Deleted text regarding ECOG 
performance ≥ 2 
 
ECOG status changed from 0-1 to 0-2 
and text added to Inclusion criteria #2 
“able to tolerate standard of care IMRT 
treatment according to the Investigator 
assessment” 
To implement a recommendation from 
regulatory authorities and feedback from 
investigators 
5.1-Inclusion Criteria 
Updated Inclusion criteria #9 regarding 
cisplatin ineligibility criteria: 
• 
For Japanese participants, modified 
CKD-EPI creatinine formula needs 
to be referred (Appendix 12) 
• 
For participants with history of 
hearing impairment-added text to 
refer to Appendix 12 for France 
specific requirements 
 
To align with local requirements 
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Section # and Name 
Description of Change 
Brief Rationale 
• 
For participants ≥ 70 years, unfit 
according to G8 questionnaire, 
following text has been added: 
“or ineligible for cisplatin treatment 
according to national guidelines” 
To align with national guidelines defining 
participants aged >70 ineligible to cisplatin 
(i.e. UK) 
 
5.2 Exclusion Criteria 
Added the word “Recurrent” in exclusion 
criteria #4 
To clarify the exclusion of participants with 
recurrent disease in this study 
6.5.1.1 Concurrent 
Administration to 
IMRT 
Deleted text specifying time of drug 
administration “1 to 4 hours” before 
IMRT and replaced with text “in the 
morning” 
For operational ease, as specific time of 
IMRT administration is not being captured 
6.5.1.2 Dose 
Modification, 
Interruption and 
Discontinuation of 
Xevinapant / Placebo 
Treatment Table 8 
Dose modification for eGFR (using the 
CKD-EPI creatinine formula) after an 
Adverse Event 
To follow updated dose modifications rules 
from TrilynX (Study MS202359_0006 – 
Phase III study xevinapant and CRT in 
unresected LA SCCHN) 
6.5.2.2 Treatment 
Deletion of text in parenthesis in the 
sentence “Initiation of radiotherapy must 
start 4 to 8 weeks after surgery (unless 
there are healing or logistical concerns) 
on C1D1 of xevinapant / placebo” 
To align with inclusion criteria #3, that 
participants have received surgery in the 
past 4 to 8 weeks before start of treatment 
and to avoid any potential delays  
6.8.2 Medications to 
be Used with Caution 
with Xevinapant or 
Placebo Table 11 
Added the drug “Lansoprazole” 
To add commonly used medication with 
potential PK interaction with xevinapant 
8.2.3 
Electrocardiograms 
Added text: If QTcF is not automatically 
measured, it can be calculated 
separately 
For operational ease at sites 
Appendix 3-Conduct 
of the study during 
COVID-19 Pandemic” 
Updated header and text in the 
appendix to make COVID-19 
recommendations generic for all 
countries 
Section is applicable to all countries during 
COVID-19 pandemic 
Appendix 7- 
Response Evaluation 
Criteria in Solid 
Tumors (RECIST) 
Version 1.1 Applied 
to Adjuvant Studies 
of Squamous Cell 
Carcinoma of the 
Head and Neck 
Added text for collection of baseline 
photographs and reports for endoscopy 
and biopsy 
To facilitate IRC assessment of potential 
macroscopic residual disease at baseline 
Appendix 12-
Country-Specific 
Requirements  
Updated to add local requirements from 
Japan, South Korea, France and India 
 
Updated Inclusion Criteria #9 for Japan 
regarding eGFR 
 
 
To align with the various local amendments 
 
 
According to local practice guidelines, 
modified eGFR calculation formula should be 
used for Japanese participants for more 
precise evaluation of renal function 
Updated 5.1 Inclusion Criteria #11 for 
South Korea Contraception 
requirements  
To extend the contraception period to 1 year 
after radiotherapy treatment as per Korean 
Health Authority recommendation. 
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Section # and Name 
Description of Change 
Brief Rationale 
Updated 5.1 Inclusion Criteria #9 for 
France History of hearing impairment 
As per France Health Authority 
recommendation 
 
Updated Regulatory Reporting 
Requirements for Serious Adverse 
Events for India  
To include the local reporting requirements 
for serious adverse events as per feedback 
from the Indian Health Authority. 
 
Protocol Version 3.0 (17 August 2022) 
Overall Rationale for the Amendment 
The main rationale for this protocol amendment is to provide additional clarification on the 
cisplatin ineligibility criteria, revised PK sampling, and to remove the 18F-FDG-PET-scan at 
screening.  
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
 
3 Objectives and 
Estimands 
 
8.1.3 DFS Events 
and Definitions 
Added clarity regarding date for the 
primary endpoint: Disease-Free 
Survival 
To clarify that in case of disease recurrence, the 
earlier date of biopsy collection or imaging is 
used to confirm a DFS assessment 
1.1 Synopsis 
 
3 Objectives and 
Estimands 
 
9.4.1 Efficacy 
Analyses (Table 
19) 
Revised the PRO estimands to focus 
the evaluation during the on treatment 
period 
 
To align the PRO objectives with data collection 
(in particular, to account for missing data 
expectation) 
1.3 Schedule of 
Activities, Table 1 
 
5.1 Inclusion 
Criterion #6  
 
5.4 Screen 
Failures 
 
8.1 Efficacy 
Assessments and 
Procedures 
 
 
Removed 18F-FDG-PET scan at 
screening visit 
18F FDG-PET scan soon after major surgery 
may cause false positive results and causes 
additional complexity. It is therefore not 
considered a standard assessment in this 
setting. 
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1.3 Schedule of 
Activities, Table 2 
Added notes in the row for blood 
hematology about requirement of local 
tests for confirming eligibility for 
treatment 
To ensure consistency across protocol 
1.3 Schedule of 
Activities, Table 2 
and Table 6 
 
 
 
 
 
 
 
6.5.1 Xevinapant 
or Placebo Dosing 
and Administration 
 
8.2.6 Patient Diary 
Adjusted row for collection of additional 
PK samples at C5D1 and C6D1 in 
Table 2 
 
In Table 6, added new rows for sample 
collection at the additional timepoints, 
C5D1 and C6D1.Also, for timepoint 
C2D8, window period for postdose 
sample collection added  
 
 
Added clarification, regarding reporting 
of time of last dosing prior to PK 
sample, for PK timepoints C3D8, 
C4D1, C5D1 and C6D1 
To collect information for Population-
Pharmacokinetics as per regulatory request  
4.2 Scientific 
rationale for Study 
Design 
 
5.1 Inclusion 
criteria 
 
 
 
 
 
 
10. References 
 
Added clarification on cisplatin 
ineligibility criteria with regard to renal 
clearance, hearing impairment, 
peripheral neuropathy, ECOG  
 
 
 
 
 
 
 
 
Updated with additional references in 
rationale 
To clarify that participants with an eGFR of 
50 to 59 ml/min who are deemed ineligible for 
any cisplatin treatment based on current clinical 
practice can be included in this study 
 
To clarify that participants with a Grade ≥ 2 
audiometric hearing loss or tinnitus, or 
peripheral neuropathy are ineligible for cisplatin 
 
To clarify that participants with ECOG ≥ 2 have 
a high risk factor for toxicities and are therefore 
excluded 
 
To provide justification for rationale 
4.2 Scientific 
rationale for Study 
Design 
Added text for clarification on R1 
resection 
To clarify that only participants with 
microscopically close margin ≤ 1 mm or 
microscopic positive margin (R1) are included in 
the study 
5.1 Inclusion 
criteria 
Added text for lower limit of eGFR 
(inclusion criteria # 9) and inclusion 
criterion# 10 was modified to clarify the 
interpretation of inclusion criterion #9 
 
To clarify that participants with severe renal 
impairment should not be included in the study, 
and therefore they should have an eGFR ≥ 
30 mL/min/1.73m² 
5.2 Exclusion 
criteria 
Added the word “interventional” in 
exclusion criteria no.21 
To clarify that only participants who took part in 
an interventional clinical study within 28 days 
prior to screening or during participation in this 
study must be excluded from this study 
8 Study 
Assessments and 
Procedures 
Updated text for increase in volume of 
blood from “55 mL” to “60 mL” for 
24- hour period and for “120 mL” to 
“130 mL” for 4-week period  
To update the blood volume for the additional 
PK samples 
8.1 Efficacy 
Assessments and 
Procedures 
Added requirement of sending 
diagnostic pre-surgery CT/MRI scan 
and recent pre-surgery or baseline 
PET-CT scan, if available, to IRC 
To facilitate IRC assessment of any potential 
macroscopic residual disease at baseline 
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Protocol Version 2.0 (28 April 2022) 
Overall Rationale for the Amendment 
The main rationale for this protocol amendment is to clarify how the DFS primary endpoint will 
be assessed for statistical analysis, and to clarify the collection of AEs and AESIs. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities, 
Table 4  
Adjusted row to collect AE up to FU28 
visit. Added updated section number.  
Adjusted for more clarity Table 4 and Table 5 and 
Section 8.3.7. 
 
1.3 Schedule of 
Activities, 
Table 5 
Changed “≤ 3 months” into “at least 
every 3 months”. 
Adjusted row to collect AESI up to EOS. 
Added updated section number. 
Added additional information in the 
notes for collection of AEs for 
participants who move to OS FU phase 
early. 
To clarify that visits in the EOS period should 
occur at least every 3 months.  
Adjusted for more clarity Table 4 and Table 5 and 
Section 8.3.7. 
To allow for monitoring of such events during 
28 months after treatment as adequate. No 
collection of AEs after a participant needs next 
line anticancer treatment since Sponsor would 
have limited access to participants and their data 
(participant may change to another study or 
another hospital). 
4.2 Scientific 
Rationale for 
Study Design 
‘DFS as assessed by IRC will be used 
in an alpha-controlled supplementary 
analysis’: ‘centralized independent 
review’ was deleted from sentence. 
Consistency across protocol. 
5.2 Exclusion 
Criteria 
Exclusion of participants with major 
surgery changed from 6 weeks to 
4 weeks prior to start of study 
intervention. 
4 weeks is considered sufficient for participants to 
recover from surgery.  
6.3.2 Blinding 
Added IRC to list of blinded personnel 
and deleted corresponding paragraph. 
In a double-blind study, IRC is no additional 
measure of blinding. 
8.1.1. Radiological 
Assessment 
Added text that the Sponsor may 
discontinue image transfer to vendor 
once no further analyses by IRC 
assessment are planned. 
To stop sending images to vendor if no further 
analyses by IRC assessments are planned. 
 
8.1 2 Clinical 
Assessment and 
 
Added requirement of submitting 
endoscopy photographs to IRC 
For all suspected disease relapse that is 
detected clinically (by endoscopy), objective 
evidence supporting disease relapse must be 
collected and submitted to IRC 
8.2.3 
Electrocardiograms 
Added additional clarification on 
number of traces in case ECG is 
abnormal 
In case of an abnormal ECG trace, in total 3 
traces need to be collected, including the 
original abnormal trace.  
9.4.1 Efficacy 
Analyses 
Table 19 
Estimand naming and order of 
supplementary and sensitivity analyses 
have been changed 
As per Health Authority comment 
Throughout 
Minor editorial and document 
formatting revisions 
Administrative revisions implemented for clarity 
and consistency. Minor, therefore, have not 
been summarized 
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Section # and 
Name 
Description of Change 
Brief Rationale 
8.3.7 Adverse 
Events of 
Special Interest 
Inserted subheadings for each 
collection period and aligned AESI to be 
collected in these periods. 
Adapted list of late onset AESI 
Adjusted for more clarity Table 4 and 5 and 
Section 8.3.7. 
Since all AEs are collected up to FU28 visit, no 
need to specify the AESI in the first months of the 
DFS FU period. 
9.4.1 Efficacy 
Analyses, 
Table 19 
 
Replaced ‘centralized independent 
review’ by ‘IRC’; clarification that OS 
significance testing is conducted only if 
both DFS hypotheses are rejected. 
Consistency across protocol. 
9.4.4 Sequence 
of Analysis 
Figure 6 updated to include assessor of 
DFS. 
All levels of the hierarchical (alpha-
controlled) testing strategy now listed. 
Better traceability of the statistical testing 
procedure. 
 
 
 
 
 
Appendix 14 
Change in name of Medical 
Responsible 
The Medical Responsible for this study has 
changed. 
Throughout 
Minor editorial and document formatting 
revisions 
Administrative revisions implemented for clarity 
and consistency. Minor; therefore, have not been 
summarized 
 
 
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Appendix 14 
Sponsor Signature Page  
Study Title: 
A randomized, double-blind, placebo-controlled, 2-arm 
Phase III study to assess efficacy and safety of xevinapant 
and radiotherapy compared to placebo and radiotherapy 
for demonstrating improvement of disease-free survival in 
participants with resected squamous cell carcinoma of the 
head and neck, who are at high risk for relapse and are 
ineligible for high-dose cisplatin 
 
Regulatory Agency Identifying 
Numbers: 
FDA Center for Drug Evaluation and Research, 
IND: 156735 
EudraCT: 2022-001144-18 
Clinical Study Protocol Version: 
18 October 2023/Version 6.0 
I approve the design of the clinical study: 
 
____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Name, academic degree: 
 
Function/Title: 
 
Institution: 
Merck Healthcare KGaA 
Address: 
Frankfurter Str. 250 
64293 Darmstadt, Germany 
General Merck Phone Number: 
+ 49 6151 720  
General Merck Fax Number: 
Not applicable 
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Appendix 15 
Coordinating Investigator Signature Page  
Study Title: 
A randomized, double-blind, placebo-controlled, 2-arm 
Phase III study to assess efficacy and safety of xevinapant 
and radiotherapy compared to placebo and radiotherapy 
for demonstrating improvement of disease-free survival in 
participants with resected squamous cell carcinoma of the 
head and neck, who are at high risk for relapse and are 
ineligible for high-dose cisplatin 
 
Regulatory Agency Identifying 
Numbers: 
FDA Center for Drug Evaluation and Research, 
IND: 156735 
EudraCT: 2022-001144-18 
 
Clinical Study Protocol Version: 
18 October 2023/Version 6.0 
 
Site Number: 
101 
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 
laws. 
 
 
____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Name, academic degree: 
 
Function/Title: 
  
Institution: 
 
Address: 
 
Telephone number: 
 
Fax number: 
 
E-mail address: 
 
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Appendix 16 
Principal Investigator Signature Page  
Study Title: 
A randomized, double-blind, placebo-controlled, 2-arm 
Phase III study to assess efficacy and safety of xevinapant 
and radiotherapy compared to placebo and radiotherapy 
for demonstrating improvement of disease-free survival in 
participants with resected squamous cell carcinoma of the 
head and neck, who are at high risk for relapse and are 
ineligible for high-dose cisplatin 
 
Regulatory Agency Identifying 
Numbers: 
FDA Center for Drug Evaluation and Research, 
IND: 156735 
EudraCT: 2022-001144-18 
 
Clinical Study Protocol Version: 
18 October 2023/Version 6.0 
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: 
 
 
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