A Single Arm, Open Label, Phase 1b Study of Xevinapant in Combination With Weekly Cisplatin and Intensity-modulated Radiotherapy to Assess Safety and Tolerability in Participants With LA SCCHN, Suitable for Definitive Chemoradiotherapy (HyperlynX)
Phase: PHASE1
Conditions: Head and Neck Cancer
Sponsor: EMD Serono Research & Development Institute, Inc.

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
1/154 
 
 
Clinical Study Protocol  
Title Page  
Clinical Study Protocol Title: 
A Single Arm, Open label, Phase 1b Study of 
Xevinapant in Combination With Weekly 
Cisplatin and Intensity-modulated Radiotherapy to 
Assess Safety and Tolerability in Participants 
With Locally Advanced Squamous Cell 
Carcinoma of the Head and Neck, Suitable for 
Definitive Chemoradiotherapy 
Study Number: 
MS202359_0025 
Protocol Version: 
27 November 2023/Version 2.0 
Merck Compound: 
Not applicable 
Merck Registered Compound Name in 
Japan: 
Not applicable 
Study Phase: 
Phase 1b 
Brief Title: 
Phase 1b safety study of xevinapant, weekly 
cisplatin, and radiotherapy in participants with 
unresected LA SCCHN  
Acronym: 
HyperLynX 
Coordinating or Principal Investigator: 
 
Nabil F. Saba MD, FACP, 
Professor and Vice Chair, Hematology, and 
Medical Oncology 
The Lynne and Howard Halpern Chair in Head 
and Neck Cancer Research, 
Co-Director H&N CA Multidisciplinary Program 
Winship Cancer Institute 
Emory University  
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
2/154 
 
 
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 Strasse 250 
64293 Darmstadt, Germany 
In the US and Canada: 
EMD Serono Research & Development Institute, 
Inc. 
an affiliate of Merck KGaA, Darmstadt, Germany 
45 A Middlesex Turnpike 
Billerica, MA, 01821, USA 
 
Regulatory Agency Identifying 
Numbers: 
IND:143330 
EU trial number: 2023-505796-76-00 
Keywords 
Unresected, Combination with CRT, Stage III, 
Stage IVA, Stage IVB, oropharynx, hypopharynx, 
and larynx 
Protocol Amendment Summary of Changes 
Protocol History 
 
Version Number 
Type 
Version Date 
2.0 
Global Amendment 
27 November 2023 
1.0 
Original Protocol 
17 May 2023 
Protocol Version 2.0 (27 November 2023) 
Overall Rationale for the Amendment 
The main rationale for this protocol amendment is to add inflammatory cutaneous adverse events 
as adverse event of special interest, to incorporate HA feedback on audiometric hearing tests 
during the treatment period and follow up period, on contraceptive period after cisplatin treatment, 
and to update the definitions of DLT-like events and add study stopping rules. Additionally, 
updates have been made to resolve identified discrepancies in the protocol. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
activities, Table 1, 
Table 2, and 
Table 3 
Added weekly audiometry testing prior to weekly 
cisplatin dosing, if clinically indicated. 
As per request from health 
authority 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
3/154 
 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Inclusion 
criterion #9 
To harmonize the period for contraceptive measures 
for chemotherapy across the protocol as per local 
guidelines and local product information. 
As per request from health 
authority and IRB 
5.2 Exclusion 
criterion #15 
To change time period when a live attenuated 
vaccines can be used prior to start study intervention 
from 30 to 28 days. 
To harmonize with Section 
6.8.3.1 Prohibited Medications 
with Xevinapant 
6.5.2 
Chemotherapy, 
and 6.8.1.1 
Antiemetics 
Update on proposed antiemetic regimens. 
Dexamethasone is proposed at 8 mg for Day 1 and 
4 mg for Days 2 and 3 after cisplatin infusion; 
aprepitant is proposed to be taken only on Days 1 and 
2 after cisplatin infusion. 
Alternative dosage/schedule for 
anti-emetic regimens are 
proposed to mitigate DDI risks 
8.2.5 Safety 
Monitoring 
Committee 
To add that the SMC can decide to stop the study in 
case of unacceptable toxicities or treatment related 
deaths. 
As per request from health 
authority 
8.2.5.1 Definition 
of DLT-like events 
Updated the definition of DLT-like events to include 
Hy’s law cases and Grade ≥ 3 lab abnormalities, and 
exceptions to the Grade ≥ 3 lab abnormalities. 
As per request from health 
authority 
8.2.7 Audiometry 
To add section for audiometry testing, which is to be 
done prior to weekly cisplatin dosing and follow up if 
clinically indicated. 
As per request from health 
authority 
8.3.4 Pregnancy 
Updated reporting of pregnancy information in the 
CRF. 
Updated in line with Sponsor 
requirements 
10 Reference list 
Added new reference. 
Updated to include the current 
reference list 
Appendix 2 
Update RECIST criteria to remove the recording of 
non-target lesions in evaluation visits. 
Updated in line with study 
requirements 
Appendix 3 
Updated the section to harmonize the period for 
contraceptive measures for chemotherapy across the 
protocol as per local guidelines and local product 
information. 
As per request from health 
authority and IRB 
Appendix 5 Study 
Governance 
Added paragraph on applicable regulations to protect 
personal data and updated the composition of SMC. 
Added information to clarify 
follow-up if regulations to protect 
personal data are not followed, 
and to allow additional SMC 
members, if considered 
necessary 
Appendix 7 
Adverse Event 
Updated information on use of paper form for SAE 
reporting, reporting of pregnancies, and reporting of 
AESIs. 
Updated in line with Sponsor 
requirements 
Appendix 8 
Clinical 
Laboratory Test 
Removal of alcohol and drug screen. 
Assessment not needed for this 
patient population 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
4/154 
 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout 
document 
Minor editorial and document formatting revisions. 
For clarity 
 
- Confidential – 
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published, or used without express 
permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2023 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
5/154 
 
 
Table of Contents  
Table of Contents  ..............................................................................................................5 
Table of Tables 
 ..............................................................................................................9 
Table of Figures 
 ............................................................................................................10 
1 
Protocol Summary ..............................................................................11 
1.1 
Synopsis ..............................................................................................11 
1.2 
Schema ................................................................................................15 
1.3 
Schedule of Activities .........................................................................16 
2 
Introduction .........................................................................................28 
2.1 
Study Rationale ...................................................................................28 
2.2 
Background .........................................................................................29 
2.3 
Benefit/Risk Assessment ....................................................................30 
2.3.1 
Risk Assessment .................................................................................32 
2.3.2 
Benefit Assessment .............................................................................34 
2.3.3 
Overall Benefit: Risk Conclusion .......................................................35 
3 
Objectives and Estimands ...................................................................36 
4 
Study Design .......................................................................................38 
4.1 
Overall Design ....................................................................................38 
4.2 
Scientific Rationale for Study Design ................................................39 
4.2.1 
Patient Input into Study ......................................................................40 
4.3 
Justification for Dose ..........................................................................41 
4.4 
End of Study Definition ......................................................................42 
5 
Study Population .................................................................................43 
5.1 
Inclusion Criteria ................................................................................43 
5.2 
Exclusion Criteria ...............................................................................46 
5.3 
Lifestyle Considerations .....................................................................50 
5.3.1 
Meals and Dietary Restrictions ...........................................................50 
5.4 
Screen Failures ....................................................................................50 
5.5 
Criteria for Temporarily Delaying Enrollment/Administration of 
Study Intervention ..............................................................................51 
6 
Study Intervention(s) and Concomitant Therapies .............................51 
6.1 
Study Intervention(s) Administration .................................................51 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
6/154 
 
 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability .....................................................................................53 
6.3 
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................54 
6.3.1 
Study Intervention Assignment ..........................................................54 
6.4 
Study Intervention Compliance ..........................................................55 
6.5 
Dose Modification ..............................................................................55 
6.5.1 
Xevinapant Administration .................................................................55 
6.5.1.1 
Concurrent Administration to Chemotherapy and IMRT ...................56 
6.5.1.2 
Dose Modification, Interruption, and Discontinuation of 
Xevinapant Treatment ........................................................................56 
6.5.1.3 
End of Xevinapant Treatment .............................................................73 
6.5.2 
Chemotherapy .....................................................................................73 
6.5.2.1 
Dose Modification, Interruption, and Discontinuation of 
Chemotherapy .....................................................................................74 
6.5.2.2 
End of Chemotherapy .........................................................................74 
6.5.3 
Radiotherapy .......................................................................................75 
6.5.3.1 
General Considerations .......................................................................75 
6.5.3.2 
Treatment ............................................................................................75 
6.5.3.3 
Treatment Interruption ........................................................................77 
6.5.3.4 
Management of Acute “in Radiation Field” Toxicity .........................77 
6.5.3.5 
End of Radiotherapy ...........................................................................78 
6.6 
Continued Access to Study Intervention After the End of the 
Study ...................................................................................................78 
6.7 
Treatment of Overdose .......................................................................78 
6.8 
Concomitant Therapy .........................................................................78 
6.8.1 
Permitted Medicines ...........................................................................79 
6.8.1.1 
Antiemetics .........................................................................................79 
6.8.2 
Medications to be Used with Caution With Xevinapant ....................80 
6.8.3 
Prohibited Medicines ..........................................................................81 
6.8.3.1 
Prohibited Medications with Xevinapant ...........................................81 
6.8.3.2 
Prohibited Medications and Medications to be Used with Caution 
with Cisplatin or Carboplatin ..............................................................84 
6.8.4 
Other Interventions .............................................................................85 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
7/154 
 
 
6.8.4.1 
Nutritional Support .............................................................................85 
6.8.4.2 
Dental Care .........................................................................................85 
6.8.4.3 
Pain .....................................................................................................85 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...............................................................86 
7.1 
Discontinuation of Study Intervention................................................86 
 
 
 
 
7.1.3 
Temporary Discontinuation ................................................................87 
7.1.4 
Rechallenge .........................................................................................87 
7.1.4.1 
Study Intervention Restart or Rechallenge After Liver Stopping 
Criteria Are Met ..................................................................................87 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................87 
7.3 
Lost to Follow-Up...............................................................................88 
8 
Study Assessments and Procedures ....................................................89 
8.1 
Efficacy Assessments and Procedures ................................................90 
8.1.1 
Radiological Assessment ....................................................................90 
8.1.2 
Radiological/Clinical Assessment at EOT and Follow-up .................91 
8.2 
Safety Assessments and Procedures ...................................................92 
8.2.1 
Physical Examinations ........................................................................92 
8.2.2 
Vital Signs ..........................................................................................92 
8.2.3 
Electrocardiograms .............................................................................93 
8.2.4 
Clinical Safety Laboratory Tests ........................................................94 
8.2.4.1 
HPV Status in Participants with OPC .................................................95 
8.2.5 
Safety Monitoring Committee (SMC) ................................................95 
8.2.5.1 
Definition of DLT-like Events ............................................................95 
8.2.6 
Patient Diary .......................................................................................97 
8.2.7 
Audiometry .........................................................................................97 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting ............................................................................................97 
8.3.1 
Method of Detecting Adverse Events and Serious Adverse Events ...98 
8.3.2 
Follow-up of Adverse Events and Serious Adverse Events ...............98 
8.3.3 
Regulatory Reporting Requirements for Serious Adverse Events .....99 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
8/154 
 
 
8.3.4 
Pregnancy ...........................................................................................99 
8.3.5 
Cardiovascular and Death Events .....................................................100 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs ..............................................................100 
8.3.7 
Adverse Events of Special Interest ...................................................100 
 
 
 
 
8.4 
Pharmacokinetics ..............................................................................102 
8.4.1 
Blood Sampling and Bioanalysis ......................................................102 
8.4.2 
PK Parameters ..................................................................................103 
8.5 
Genetics and/or Pharmacogenomics .................................................103 
 
 
 
 
 
 
8.7 
Immunogenicity Assessments ..........................................................104 
8.8 
Health Economics .............................................................................104 
9 
Statistical Considerations ..................................................................104 
9.1 
Statistical Hypotheses .......................................................................104 
9.2 
Sample Size Determination ..............................................................104 
9.3 
Analysis Sets .....................................................................................105 
9.4 
Statistical Analyses ...........................................................................106 
9.4.1 
Efficacy Analyses .............................................................................106 
9.4.2 
Safety Analyses ................................................................................107 
9.4.3 
Other Analyses ..................................................................................107 
9.4.4 
Sequence of Analyses .......................................................................107 
10 
References .........................................................................................109 
11 
Appendices .......................................................................................112 
Appendix 1 
Abbreviations ....................................................................................113 
Appendix 2 
Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 
Applied to This Study in Locally Advanced SCCHN ......................117 
Appendix 3 
Cisplatin Administration ...................................................................124 
Appendix 4 
Cisplatin Hydration Guidelines ........................................................128 
Appendix 5 
Study Governance .............................................................................129 
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
9/154 
 
 
Appendix 6 
Contraception and Barrier Requirements .........................................135 
Appendix 7 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ..............................................137 
Appendix 8 
Clinical Laboratory Tests .................................................................144 
Appendix 9 
Recommended Dental/Oral Evaluations ...........................................146 
Appendix 10 
Conduct of the Study During the COVID-19 Pandemic ..................147 
Appendix 11 
Country-specific Requirements ........................................................150 
Appendix 12 
Protocol Amendment History ...........................................................151 
Appendix 13 
Sponsor Signature Page ....................................................................152 
Appendix 14 
Coordinating Investigator Signature Page ........................................153 
Appendix 15 
Principal Investigator Signature Page ...............................................154 
 
Table of Tables  
Table 1 
Schedule of Activities: Screening .......................................................20 
Table 2 
Schedule of Activities (Combination Treatment Period [Cycles 1 
to 3]) ....................................................................................................21 
Table 3 
Schedule of Activities: Monotherapy Period (Cycle 4 till Cycle 6) 
and Follow-up Period .........................................................................24 
Table 4 
Schedule of Activities: Pharmacokinetic Assessments ......................27 
Table 5 
Study Intervention(s)Administered ....................................................52 
Table 6 
Study Arm(s) ......................................................................................53 
 
 
 
 
 
 
 
 
 
Table 9 
Radiation Therapy Scheme .................................................................76 
Table 10 
Anesthetic and Analgesic Drugs to be Used with Xevinapant 
under Close Medical Monitoring ........................................................80 
Table 11 
Other Drugs to be Used with Xevinapant Under Close Medical 
Monitoring ..........................................................................................81 
Table 12 
Examples of Prohibited Inhibitors and Inducers of P-gp with 
Xevinapant ..........................................................................................83 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
10/154 
 
 
Table 13 
Examples of Prohibited CYP3A4/5 Sensitive Substrates with 
Xevinapant ..........................................................................................84 
Table 14 
ECG Collection Plan ...........................................................................93 
Table 15 
Sample Size Calculation ...................................................................105 
Table 16 
Analysis Set ......................................................................................105 
Table 17 
Sequence of Planned Analysis ..........................................................108 
Table 18 
Response Status Definition for Target Lesions at Each Timepoint ..120 
Table 19 
Response Status Definition for Nontarget Lesions at Each 
Timepoint ..........................................................................................121 
Table 20 
Timepoint Assessment of Disease Status by Imaging for 
Participants With Measurable Disease at Baseline. ..........................122 
Table 21 
Timepoint Assessment of Disease Status by Imaging for 
Participants With Non-measurable Disease at Baseline, or due to 
Biopsy or Excision ............................................................................122 
Table of Figures  
Figure 1 
Study Diagram ....................................................................................15 
Figure 2 
Study Flow Chart ................................................................................16 
Figure 3 
Treatment Diagram and Time Window for Visits ..............................26 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
11/154 
 
 
1 
Protocol Summary  
1.1 
Synopsis  
Clinical Study Protocol Title: A Single Arm, Open label, Phase 1b Study of Xevinapant in 
Combination With Weekly Cisplatin and Intensity-modulated Radiotherapy to Assess Safety and 
Tolerability in Participants With Locally Advanced Squamous Cell Carcinoma of the Head and 
Neck, Suitable for Definitive Chemoradiotherapy 
Brief Title: Phase 1b safety study of xevinapant, weekly cisplatin, and radiotherapy in participants 
with unresected LA SCCHN 
Rationale: Xevinapant is an inhibitor of IAPs (inhibitor of apoptosis proteins) that has been shown 
in nonclinical in vitro and in vivo models to have both chemo- and radiosensitizing potential as 
well as immunomodulatory potential. In unresected LA SCCHN patients, the addition of 
xevinapant to SoC CRT using Q3W cisplatin (100 mg/m2) recently showed a statistically 
significant and clinically meaningful improvement in locoregional control at 18 months compared 
to placebo with SoC CRT. Following the 36-month analysis, PFS also showed a clinically 
meaningful improved benefit from xevinapant versus placebo. Furthermore, a clinically relevant 
improvement in 5-year OS using xevinapant combined with CRT vs the control group was recently 
presented. The current Phase 1b study aims to assess tolerability and safety of xevinapant when 
added to QW cisplatin-based (
mg/m2) concomitant CRT in the treatment of previously 
untreated participants with unresected LA SCCHN. 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
13/154 
 
 
Objectives 
Endpoints 
Further Estimand Attributes 
Ref. 
# 
PFS according to RECIST 
1.1 assessed by 
Investigator  
Population/Treatment: Same as #1 
Intercurrent Event Strategy: 
• Death within 2 missing scheduled tumor 
assessments after last evaluable 
assessment or start of study intervention 
will be considered as event (composite 
strategy) 
• Discontinuation of treatment: ignoring the 
intercurrent event (treatment policy 
strategy) 
• Start of subsequent anticancer therapy: 
ignoring events after the start of a new 
anticancer therapy (hypothetical strategy) 
Population-level Summary: Kaplan-Meier 
estimates including associated statistics 
4 
Locoregional control (LRC) 
according to RECIST 1.1 
assessed by Investigator  
Population/Treatment: Same as #1 
Intercurrent Event Strategy: 
• Death: Assessments before death will be 
used (treatment policy strategy) 
• Discontinuation of treatment: ignoring the 
intercurrent event (treatment policy 
strategy) 
• Start of new anticancer therapy: ignoring 
events after the start of a new anticancer 
treatment (hypothetical strategy) 
Population-level Summary: Same as #4 
5 
To evaluate time to 
subsequent cancer 
treatments in participants 
treated with xevinapant 
when added to weekly 
cisplatin-based CRT in LA 
SCCHN 
Time to subsequent 
systemic cancer treatments 
Population/Treatment: Same as #1 
Intercurrent Event Strategy/ Population-level 
Summary: Same as #5 
6 
 
Overall Design: 
This is a multicenter, single arm, open label, Phase 1b study. 
Brief Summary: The purpose of this study is to evaluate the tolerability and safety of xevinapant 
when added to weekly cisplatin-based concurrent CRT in the treatment of participants with 
unresectable locally advanced squamous cell carcinoma of the head and neck, suitable for 
definitive chemoradiotherapy. 
Study details include: 
• Study duration: participants to be followed until the last on-study participant reaches his/her 
18-month post-first treatment visit (EOS) 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. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
14/154 
 
 
• Visit frequency: One to 3 visits a week during combination therapy period, once every 3 weeks 
during xevinapant monotherapy period, and every 3 months during the Follow-up period until 
EOS. 
Since treatment is limited to 18 weeks no continued availability of xevinapant outside of the study 
protocol is foreseen. 
Number of Participants: A total of approximately 40 participants will be assigned to study 
intervention. It is anticipated to conduct the study in the US, Europe, and Asia-Pacific. 
Study Intervention Groups and Duration: 
Participants who meet the eligibility criteria will be enrolled and will receive the following 
treatment: 
• 3 cycles of xevinapant (oral solution 
 mg/day from Day 1 to 14, per 3-week cycle) + weekly 
cisplatin (
 mg/m2 for 7 weeks on Cycle 1 Day 2 (C1D2), C1D9, C1D16, C2D2, C2D9, 
C2D16, and C3D2) + IMRT (70 Gy in 35 fractions, 2 Gy/fraction, 5 days/week), followed by 
3 cycles of monotherapy of xevinapant (
mg/day from Day 1 to 14, per 3-week cycle). 
Data and Safety Monitoring /Other Committee: Yes 
A Safety Monitoring Committee (SMC) has been appointed for this study. The SMC consists of 
Sponsor representatives and the Coordinating Investigator. 
 
 
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
15/154 
 
 
1.2 
Schema  
Figure 1 
Study Diagram  
 
 
D=day, DLT=dose-limiting toxicity, EOS=end of study, EOT=end of treatment, IMRT=intensity-modulated radiation 
therapy, QW=once weekly. 
a. 
Each cycle consists of 3 weeks. 
b. 
Follow-up period starts after EOT visit and runs up to 18 months after last on-study participant first dosing. 
Note: Round filled shape at Day 1 indicates start of treatment. 
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, and Table 4. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
17/154 
 
 
Screening procedures will start once the participant has signed the ICF and can last up to 28 days. 
Intravenous (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 study intervention starts. Dental 
examination, audiometry, HBV/HCV/HIV tests, fiberoptic endoscopy, and 18F-FDG-PET 
(18F-FDG-PET/CT is also allowed) scan performed within 4 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 treatment start will be used as baseline (for each participant, the same radiological method must 
be used throughout the study). Further details on imaging are provided in Table 1, Table 2,  
Table 3, and Section 8.1. 
During screening and after study intervention start, laboratory assessments and pregnancy tests 
should be performed by a local laboratory according to instructions provided in Section 8.2.4. 
A participant will be considered as eligible to receive the study interventions after they have signed 
the ICF and all eligibility criteria have been met. Study intervention administration starts with 
combination treatment on C1D1. The IMRT plan must be reviewed by the RT-QA Review Center 
prior to the start of C1D1. 
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 
on the C1D1 date. The treatment diagram and time windows for visits during the treatment period 
are presented in Figure 3. 
 
 
 
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
18/154 
 
 
Adequate hydration must be maintained pre- and post-cisplatin infusion according to the following 
schedule (see Appendix 4 for detailed instructions): 
 
Pre Infusion 
Post Infusion 
Minimum 2 to 3 hours prior to administration of cisplatin 
until a minimum of 2 hours after the administration of 
cisplatin 
The EOT visit will be performed 14 days (± 7 days) after last study intervention administration 
(i.e. xevinapant, cisplatin, 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. In case of premature treatment discontinuation, imaging and clinical tumor assessments 
must be performed according to original schedule (Week 20 for EOT assessment and every 
3 months thereafter). 
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 follow-up period will start after the EOT visit. The follow-up period must be performed 
according to the planned visit schedule within the permitted visit windows. Participants without 
any progression, treatment failure, local, or distant relapse, second cancers, or death will be 
followed until the last on-study participant reaches their 18-month post-first treatment visit (EOS), 
or a decision to end the study has been triggered, or until premature discontinuation from study, 
whichever occurs first. The same is applicable for participants who prematurely discontinue study 
treatment without disease progression (e.g. unacceptable toxicity). Participants with confirmed 
disease progression will discontinue the study. 
At the EOS, all remaining participants will have an EOS visit unless their last follow-up visit was 
done less than 6 weeks before. 
During the follow-up period, each study visit day and allowed time windows will be based on the 
C1D1 date. 
After completion of the follow-up period, participants who have not discontinued the study 
prematurely will undergo the EOS assessments ([date of the 18-month visit of the last on-study 
participant] ± 1 month) and will be considered as having completed the study (see Section 7.2). 
If the last on-study participant completes the follow-up (18 months after C1D1), their EOS visit 
will be performed at the same time as their 18-month visit. In case of premature discontinuation 
from the study including confirmed disease progression, the participant’s EOS visit will be 
performed when they discontinue from the study. 
The following schedules of activities and as assessments are presented: 
Table 1: Screening 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
19/154 
 
 
Table 2: Combination Treatment Period (Cycles 1 to 3) 
Table 3: Monotherapy Period (Cycles 4 to 6) and FU/EOS Visits 
Figure 3: Treatment Diagram and Time Windows for Visits 
Table 4: Schedule of Pharmacokinetic Activities 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
23/154 
 
 
AESI = adverse events of special interest, CxD1 = Cycle x Day 1, ECG = electrocardiogram, ECOG PS = Eastern Cooperative Oncology Group Performance 
Status, CT = Computed Tomography, IMRT = Intensity-modulated radiation therapy, MRI = Magnetic Resonance Imaging, PK = pharmacokinetic, SAE = serious 
adverse event. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
26/154 
 
 
Figure 3 
Treatment Diagram and Time Window for Visits  
 
C=cycle, D=day, EOT=end of treatment, IMRT=intensity-modulated radiation therapy, QW= once a week, W=week. 
a. 
On days when IMRT is to be administered, xevinapant 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 and C1D2 are triggered by the first 
administration of xevinapant and QW cisplatin, respectively. These visits should be performed on consecutive days. 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, Table 2, and,  
c. 
Table 3). 
d. 
Xevinapant once daily from D1 to D14 of each cycle (solid red boxes)
 
 
e. 
Cisplatin-based chemotherapy weekly on C1D2, C1D9, C1D16, C2D2, C2D9, C2D16, and C3D2 (see also Section 6.5.2). For participants not eligible to 
continue with QW cisplatin after dose reduction switch to carboplatin at the next scheduled chemotherapy administration. 
f. 
IMRT should be delivered in 35 fractions over 7 weeks, 5 fractions weekly (solid yellow boxes). If IMRT is put on hold due to safety or administrative reason, 
the 7 weeks of IMRT can be administered until Study Week 9 (dotted yellow boxes) (also see Section 6.5.3). 
g. 
The EOT visit will be performed 14 days (± 7 days) after last study intervention administration (i.e. xevinapant, chemotherapy, 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.
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
27/154 
 
 
Table 4 
Schedule of Activities: Pharmacokinetic Assessments  
Treatment Day 
Timepoint 
Xevinapant PK Sampling 
C1D2 
Predose xevinapant 
(window: less than 1 hour prior to dosing) 
X 
C1D2 
End of cisplatin infusion 
(window: less than 30 min after end of infusion) 
X 
C1D9 
Predose xevinapant 
(window: less than 1 hour prior to dosing) 
X 
C1D9 
1-2 hours after end of cisplatin infusion 
X 
C2D2 
Predose xevinapant 
(window: less than 1 hour prior to dosing) 
X 
C2D2 
1-2 hours after end of cisplatin infusion  
X 
CXDX=Cycle X Day X, IMRT= Intensity modulated radiation therapy, eCRF= electronic case report form, 
PK=pharmacokinetic. 
 
 
On all PK days (C1D2, C1D9, and C2D2), participants take xevinapant at the hospital to ensure predose collection for 
xevinapant PK at the predose timepoint. On PK days, record time of oral xevinapant dose, volume of xevinapant 
dose, time of the start and end of cisplatin infusion and time of PK sampling in eCRF. 
In addition, record times and volumes of xevinapant dose taken 1 day prior to PK days (such as doses at C1D1, 
C1D8, and C2D1) in eCRF. 
* In case of switch to carboplatin, timepoint is after end of carboplatin infusion.  
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
28/154 
 
 
2 
Introduction  
Xevinapant is a novel, orally available inhibitor 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 (Matzinger 2015). The value of adding xevinapant to conventional Q3W 
high-dose cisplatin-based chemoradiotherapy in the treatment of previously untreated patients with 
unresected LA SCCHN was recently investigated in a Phase 2 study (Sun 2020) and its findings 
are currently being confirmed in a Phase 3 study (Debio 1143-SCCHN-301/MS202359_0006 
[TrilynX], NCT04459715). 
This study aims to assess safety and tolerability of xevinapant when added to QW cisplatin-based 
chemoradiotherapy (CRT) in the treatment of previously untreated patients with unresected LA 
SCCHN. 
Detailed information on the chemistry, pharmacology, efficacy, and safety of xevinapant is in the 
IB. 
2.1 
Study Rationale  
Head and neck cancer is a common cancer; representing approximately 5% of all cancer cases 
worldwide with an annual incidence of over 878,000 cases and a mortality estimated at 
444,000 deaths per year in 2020 (Sung 2021, Ferlay 2021). Definitive treatment options for LA 
SCCHN, such as surgery, can cure some patients, but can also lead to severe limitations in feeding 
(chewing and swallowing), speaking, and physical appearance that can impair social functioning 
and cause severe psychological stress (Hernandez-Vila 2016, NCCN v1 2023). Among 
conservative (nonsurgical) treatments, the most widely used standard regimen in this setting 
consists of high-dose (100 mg/m2) cisplatin administered Q3W for up to 3 cycles, combined with 
approximately 70 Gy radiation delivered in 1.8 to 2.0 Gy daily fractions. Although associated with 
increased toxicity compared to RT alone, this combination is also associated with increased local 
control rates and OS (Oun 2018). However, Q3W cisplatin (100 mg/m2) is associated with 
toxicities such as nephrotoxicity, hematotoxicity, and ototoxicity leading to low treatment 
adherence. Weekly cisplatin (
 mg/m2), administered every week (QW) for up to 7 weeks, is one 
of the commonly used alternative regimens for Q3W cisplatin (100 mg/m2) with potentially milder 
renal and ototoxicity, 
. 
Furthermore, weekly cisplatin at 
 mg/m2 requires a less intense hydration regimen compared to 
high-dose Q3W cisplatin (NCCN v1 2023, Machiels 2020, Bauml 2019). 
Xevinapant is an inhibitor 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 unresected 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 with SoC CRT (Sun 2020). 
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
29/154 
 
 
Following the 36-month analysis, PFS also showed a clinically meaningful improved benefit from 
xevinapant versus placebo. Furthermore, a clinically relevant improvement in 5-year OS using 
xevinapant combined with CRT vs the control group was recently presented (Tao 2023). The 
findings of this study are currently being confirmed in a Phase 3 study using standard Q3W 
cisplatin-based chemoradiation in combination with xevinapant (Debio 1143-SCCHN-301/ 
MS202359_0006 [TrilynX]). 
The purpose of this study is to evaluate the tolerability and safety of xevinapant when added to 
weekly cisplatin (
mg/m2) based concomitant CRT in the treatment of participants with 
unresected LA SCCHN. 
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 cancer is a common cancer 
representing approximately 5% of all cancer cases worldwide with an annual incidence of over 
878,000 cases and a mortality estimated at 444,000 deaths per year in 2020. (Sung 2021, 
Ferlay 2021). Overall, the highest incidence is observed in patients 65 years of age and older, while 
for oropharynx and nasopharynx the incidence is higher for those aged 25 to 64 years at diagnosis 
(www.rarecarenet.eu). 
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. European Society for Medical Oncology (ESMO) and National Comprehensive Cancer 
Network (NCCN) guidelines on treatment of SCCHN recommend the use of CRT when the tumor 
is unresectable or when surgery is not indicated (Machiels 2020, NCCN v1 2023). Every 3-week 
cisplatin (100 mg/m2) with concomitant RT is considered the standard systemic regimen in LA 
SCCHN across countries, irrespective of tumor location (Adelstein 2003, Gregoire 2010). 
However, Q3W cisplatin (100 mg/m2) is associated with both acute and late, often irreversible 
toxicities, which manifest as detrimental short- and long-term complications for patients and 
results in low treatment adherence and might not be an optimal treatment for many patients 
(Porceddu 2020, Espeli 2012). Older, frail patients are often unfit to receive Q3W cisplatin 
(100 mg/m2) due to renal, cardiac function, or other comorbidities. Approximately 40% of patients 
cannot complete the whole 3 planned cycles of Q3W cisplatin (100 mg/m2) due to toxicity, and a 
cumulative dose above 
 mg/m2, which seems enough to produce a therapeutic effect, might not 
be achieved for those patients (Szturz 2019). Considering SCCHN is more commonly observed in 
the elderly, development of a less toxic treatment option for those vulnerable patients remains an 
unmet need. 
Weekly cisplatin (
mg/m2) is one of the most commonly selected alternative cisplatin-based 
chemotherapy regimens due to easier administration and with a potentially better safety and 
tolerability profile compared to Q3W cisplatin (100 mg/m2) 
 
. Weekly cisplatin 
CCI
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
30/154 
 
 
(
mg/m2) is considered to show lower hematotoxicity, nausea/vomiting, and nephrotoxicity than 
the Q3W cisplatin (100 mg/m2) regimen (Szturz 2019, Sharma 2022). In addition, compliance is 
higher with a QW cisplatin (
mg/m2) regimen and associated with a significantly higher 
proportion of patients who received all planned chemotherapy cycles as compared to the Q3W 
cisplatin (100 mg/m2) regimen (Szturz 2017). 
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). 
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 
inhibitor 
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 (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 1/2 study (Debio 1143-201) and its findings are currently being 
confirmed in a Phase 3 study (Debio 1143-SCCHN-301/MS202359_0006 [TrilynX]). 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. Following the 36-month analysis, PFS also showed a clinically meaningful improved 
benefit from xevinapant versus placebo. Furthermore, a clinically relevant improvement in 5-year 
OS using xevinapant combined with CRT vs the control group was recently presented (Tao 2023). 
Overall, the safety profile of xevinapant, when added to Q3W cisplatin (100 mg/m2) and 
concurrent RT (CRT), was predictable and manageable, and did not jeopardize the delivery of 
Q3W cisplatin (100 mg/m2) concurrent with standard fractionation RT. 
This Phase 1b study aims to evaluate the tolerability and safety of xevinapant when added to QW 
cisplatin-based CRT in the treatment of participants with unresected LA SCCHN. 
Refer to the IB for further details on other non-LA SCCHN Phase 1 studies and on Study Debio 
1143-201. 
2.3 
Benefit/Risk Assessment  
Available clinical data with xevinapant originates from studies with participants and patients, 
presenting different locally advanced or advanced solid tumors or poor prognosis AML, who 
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
31/154 
 
 
received xevinapant as a monotherapy or in combination with other anticancer medicines with or 
without radiotherapy. 
As of 31 July 2022, 314 participants with a malignant disease (excluding participants from the 
blinded Study Debio 1143-SCCHN-301/MS202359_0006 [TrilynX] and the Investigator-initiated 
Study CATRIPCA) and 107 healthy participants have received at least 1 dose of xevinapant 
(ranging from
 mg/day in 3 main different schedules: D1 to 5 Q3W, D1 to 14 Q3W, or D1 
to 10 and D15 to 24 Q4W). When xevinapant was given as a single agent, the MTD was not 
reached up to doses of 
mg/day in short-course regimens (D1 to 5 Q3W) or 
mg/day in 
extended dosing schedules (D1 to 14 Q3W). 
The observed toxicities were in line with those expected in patients with advanced solid tumors, 
and/or with those observed in patients treated with CT or CRT regimen alone. Importantly, no 
relevant hematological toxicities other than mild anemia have been reported in studies with 
xevinapant single agent or in noncytotoxic containing combinations (e.g. immunotherapy with 
avelumab, nivolumab, or pembrolizumab). 
Based on the safety data of the Phase 1 and Phase 2 studies, xevinapant doses of up to 
mg/day 
were safely combined with either CT, RT, or both. When used in combination with CT or CRT, 
xevinapant appears to be equally well tolerated as CT or CRT alone and is not associated with an 
increased frequency of drug-related treatment discontinuation. Taking into account data from the 
placebo-controlled Study Debio 1143-201B, where xevinapant or placebo were administered in 
association with Q3W cisplatin-based CRT (100 mg/m2), an increased frequency of ALT increase, 
tinnitus, dysphagia, weight decrease, mucosal inflammation, radiation skin injury, nausea, and 
vomiting were observed in the xevinapant arm. Nevertheless, the predominant toxicities were 
generally mild and/or largely reversible; could be monitored by routine clinical examinations; and 
were manageable by dose delay, dose reduction, and/or supportive care. 
The safety and efficacy of xevinapant (at the recommended Phase 2 dose of 
mg/day D1 to 14 
Q3W) in combination with high-dose platinum-based CRT in previously untreated patients with 
LA SCCHN, is currently being investigated in the randomized double-blind placebo-controlled 
Phase 3 Study Debio 1143-SCCHN-301/MS202359_0006 (TrilynX). 
 
 
 
 
 
 
 
 
 
Additionally, participants in this study will be treated with QW cisplatin, which is considered to 
have a better safety profile than Q3W cisplatin (100 mg/m2), especially for hematotoxicity, nausea, 
and nephrotoxicity (Szturz 2019). Therefore, combination of xevinapant + QW cisplatin 
(
 mg/m2) based CRT is expected to have comparable or better tolerability than xevinapant + 
Q3W cisplatin (100 mg/m2). 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
32/154 
 
 
Based on the available clinical data to date, the conduct of the study, as specified in this protocol, 
is considered justifiable. 
2.3.1 
Risk Assessment  
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
33/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
34/154 
 
 
2.3.2 
Benefit Assessment  
The clinical proof of concept of xevinapant in patients with unresected LA SCCHN has been 
demonstrated by the Phase 2 Study Debio 1143-201. Based on the potential for xevinapant to act 
as a chemo- and/or radiosensitizer and immune-modulator, 
 
 
 
 
 
When xevinapant was administered in combination with CRT in LA SCCHN patients (Study 
Debio 1143-201B), a statistically significant and clinically relevant improvement was observed in 
terms of LRC at 18 months as well as clinically relevant improvements in PFS and OS. The 
24-month analysis of Study Debio 1143-201B demonstrated that the odds for LRC at 18 months 
after completing treatment is 2.5 times higher in patients (all heavy smokers, approximately 90% 
of OPC patients HPV-negative, 85% Stage IVa or IVb) treated with xevinapant compared with 
patients having received a placebo (odds ratio [95%CI]: 2.74 [1.15; 6.53]). 
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
35/154 
 
 
In addition, a risk reduction of 67% for disease progression or death was observed in patients 
having been treated with xevinapant compared with patients having received a placebo, 
demonstrating clinically meaningful improvement in PFS (hazard ratio [95%CI]: 0.33 [0.17; 0.67]; 
p = 0.0019). The PFS rate at 36 months after treatment initiation was 72% in the xevinapant arm 
and 36% in placebo arm. The median PFS was not reached in the xevinapant arm (95% CI: 37.4; 
Not Evaluable) versus 16.9 months (95% CI: 7.5; 36.1) in the placebo arm. 
Xevinapant combined with CRT showed also a clinically relevant improvement in OS compared 
to the control group. The OS rate at 5 years (Kaplan-Meier estimate) was 53% (95% CI: 37; 66) 
in the xevinapant arm versus 28% (95% CI: 15; 42) in the placebo arm, reflecting a 53% reduction 
in the risk of mortality of any cause in the xevinapant arm compared to the placebo arm 
(HR = 0.47, [95% CI: 0.27; 0.84], p = 0.0101) (refer to the current version of the IB for further 
details). 
2.3.3 
Overall Benefit: Risk Conclusion  
Overall, the toxicities of a study with xevinapant in combination with cisplatin and RT are deemed 
to be predictable and manageable. Considering the measures taken to minimize the risk to 
participants in this study, the potential risks identified in association with xevinapant are justified 
by the anticipated benefits that may be afforded to participants with unresected LA SCCHN. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
37/154 
 
 
Objectives 
Endpoints 
Further Estimand Attributes 
Ref. 
# 
To evaluate clinical activity 
parameters using 
Response Evaluation 
Criteria in Solid Tumors 
(RECIST) v 1.1 
Objective Response (OR) 
according to RECIST 1.1 
assessed by Investigator 
Population/Treatment: Same as #1 
Intercurrent Event Strategy: 
• Discontinuation of treatment: ignoring the 
intercurrent event (treatment policy 
strategy) 
• Start of new anticancer therapy: ignoring 
assessments after the intercurrent event 
(while not treated with new anticancer 
therapy strategy) 
• Progression according to RECIST 1.1: 
assessments up to the intercurrent event 
(while not progressed strategy) 
Population-level Summary: Response rates 
(i.e. CRR, ORR) including associated 
statistics 
3 
PFS according to RECIST 
1.1 assessed by 
Investigator  
Population/Treatment: Same as #1 
Intercurrent Event Strategy: 
• Death within 2 missing scheduled tumor 
assessments after last evaluable 
assessment or start of study intervention 
will be considered as event (composite 
strategy) 
• Discontinuation of treatment: ignoring the 
intercurrent event (treatment policy 
strategy) 
• Start of subsequent anticancer therapy: 
ignoring events after the start of a new 
anticancer therapy (hypothetical strategy) 
Population-level Summary: Kaplan-Meier 
estimates including associated statistics 
4 
Locoregional control (LRC) 
according to RECIST 1.1 
assessed by Investigator  
Population/Treatment: Same as #1 
Intercurrent Event Strategy: 
• Death: Assessments before death will be 
used (treatment policy strategy) 
• Discontinuation of treatment: ignoring the 
intercurrent event (treatment policy 
strategy) 
• Start of new anticancer therapy: ignoring 
events after the start of a new anticancer 
treatment (hypothetical strategy) 
Population-level Summary: Same as #4 
5 
To evaluate time to 
subsequent cancer 
treatments in participants 
treated with xevinapant 
when added to weekly 
cisplatin-based CRT in LA 
SCCHN 
Time to subsequent 
systemic cancer treatments 
Population/Treatment: Same as #1 
Intercurrent Event Strategy/ Population-level 
Summary: Same as #5 
6 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
39/154 
 
 
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, total of 18 weeks), and a 
follow-up period. Each treatment cycle consists of 3 weeks. 
Participants will be followed up until the last on-study participant 
reaches their 18-month visit or until premature discontinuation 
from study, whichever occurs first  
Provisions for Study 
Extension or Entry into 
Roll-Over Studies 
Not applicable 
Adaptive Aspects of 
Study Design 
Not applicable 
Once a participant has signed the ICF, an identification number will be assigned to the participant 
and the study-related screening procedures will be started. Upon confirmation of eligibility, 
participants will be enrolled and will receive the following treatments: 
• 3 cycles of xevinapant (oral solution 
 mg/day from Day 1 to 14, per 3-week cycle) + QW 
cisplatin for 7 weeks 
 mg/m2 on Cycle 1 Day 2 (C1D2), C1D9, C1D16, C2D2, C2D9, 
C2D16, and C3D2) + IMRT (70 Gy in 35 fractions, 2 Gy/fraction, 5 days/week), followed by 
3 cycles of monotherapy of xevinapant (
mg/day from Day 1 to 14, per 3-week cycle). 
The schedule of concurrent administration of xevinapant, cisplatin, and IMRT is presented in the 
SoA (Table 2,  
Table 3, and the treatment diagram (Figure 3). 
It is planned to enroll approximately 40 adult participants of all sexes such that approximately 
38 DLT-like evaluable participants are anticipated to be obtained. In case participants drop out of 
the study for reasons other than DLT-like events earlier than 5 weeks after start of treatment, 
additional participants may be enrolled to ensure 38 evaluable participants in the DLT analysis set. 
The primary analysis is planned when at least 38 participants meet at least 1 of the following 
criteria (see Section 9.4.4): 
• Experience at least 1 DLT-like event, regardless of the administered amount of study 
intervention/completion in the DLT-like assessment period. 
• Receive at least 60% of the planned cumulative dose of xevinapant and cisplatin during the 
DLT-like assessment period and either complete the DLT-like assessment period or discontinue 
study or study treatment for non-AE-related reasons. 
4.2 
Scientific Rationale for Study Design  
Target Population: Unresected LA SCCHN 
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
40/154 
 
 
The target population chosen for the study is patients who are expected to significantly benefit 
from treatment with xevinapant combined with QW cisplatin-based CRT (
 mg/m2), being one 
of the alternative approaches for Q3W cisplatin-based standard CRT (100 mg/m2) in unresected 
LA SCCHN. Patients with unresectable or nonresected LA SCCHN have the poorest prognosis 
and predominantly experience locoregional failures. 
Weekly Cisplatin 
Cisplatin-based CRT is a standard treatment option, and ESMO and NCCN guidelines on SCCHN 
recommend the use of CRT when the tumor is unresectable or when surgery is contraindicated 
(Machiels 2020, NCCN 2023). Although Q3W cisplatin (100 mg/m2) is considered the standard 
systemic regimen given concurrently with radiotherapy in LA SCCHN (Adelstein 2003), there is 
currently no unanimous consensus on the optimal cisplatin regimen (Szturz 2017). Three-weekly 
cisplatin (100 mg/m2) is associated with both acute and late, often irreversible toxicities, which 
manifest as detrimental short- and long-term complications for patients and results in low treatment 
adherence and not optimal treatment for many patients (Porceddu 2020, Espeli 2012). Although 
results of controlled studies comparing Q3W vs QW cisplatin-based CRT in this population are 
still awaited, many local institutions are switching to QW cisplatin (
mg/m2) concurrently used 
with radiotherapy 
) in order 
to improve compliance and easier control of toxicity as compared to Q3W cisplatin (100 mg/m2). 
In the ongoing Phase 3 study with xevinapant, RT, and cisplatin in unresected LA SCCHN patients 
(Study Debio 1143-SCCHN-301/MS202359_0006 [TrilynX]), the Q3W cisplatin (100 mg/m2) 
regimen is being used. However, since weekly cisplatin is increasing in use in many local 
institutions, the current study will evaluate if xevinapant with QW cisplatin (
mg/m2) and RT is 
safe and tolerable to use in the definitive CRT setting. 
Single Arm Study 
This study will use a single arm, open label design. The data from this study will serve to provide 
confidence for safe administration of xevinapant in combination with QW cisplatin-based CRT in 
LA SCCHN patients and to evaluate potential efficacy of this combination. 
Primary Endpoint 
The primary endpoint of this study is DLT-like events, defined in Section 8.2.5.1. The safety and 
tolerability will be assessed during the DLT-like assessment period, which is the initial 5 weeks 
on treatment for each participant. Similar DLT definitions have been used to assess the tolerability 
and safety of xevinapant in prior studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
41/154 
 
 
4.2.1 
Patient Input into Study  
Patient interviews were conducted to understand potential barriers to participation and general 
reactions to the clinical study design for TrilynX (refer to Study Debio 1143-SCCHN-
301/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. 
Additional feedback was obtained from a Patient Advocacy meeting undertaken for the XRay 
Vision (refer to study MS202359_0002) which included patient advocates (and caregivers), who 
themselves were patients with LA SCCHN from Europe, Japan, and the US. Key learnings from 
these meetings have been recognized within this study such as streamlined patient diary and IMP 
Packaging. In addition, some patients acknowledged that they felt uncared for and isolated 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 
Xevinapant is to be administered orally without regard to food at 
 mg once daily from Day 1 
to Day 14 of a 3-week cycle for 3 cycles in combination with CRT followed by three 3-week cycles 
of xevinapant monotherapy. Individual stepwise dose reductions to 
 mg are allowed 
for the management of toxicities. 
 
 
The selected dose is supported by holistic integration of nonclinical pharmacology, clinical 
efficacy, and safety data, clinical population PK (popPK) and population PK/PD modeling and 
simulations, and exposure-response analyses for efficacy and safety (based on data from Study 
) as described in IB. 
Additional xevinapant monotherapy cycles are supported by enhanced antitumor activity with 
extended monotherapy dosing following the xevinapant + RT combination cycles in an MC38 
syngeneic mouse model. 
 
 
 
 
Cisplatin (Carboplatin, Only in Case of Cisplatin Toxicity as per Table 8) 
While the Q3W (100 mg/m2) regimen for up to 3 cycles delivered concomitantly with IMRT is 
generally considered the standard (Szturz 2017) and has been widely adopted whenever patients 
are eligible, there is currently no unanimous consensus on the optimal cisplatin regimen. 
CCI
CCI
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
42/154 
 
 
Due to the toxicity of the Q3W cisplatin (100 mg/m2) regimen, many institutions use another 
recommended regimen of cisplatin instead (QW cisplatin at 
mg/m2) 
 
 to improve compliance and easier control of toxicity as compared to Q3W 
cisplatin (100 mg/m2). A total cumulative cisplatin dose of 
mg/m2 is recommended 
(Machiels 2020), based on various studies suggesting a sufficient therapeutic effect when this 
exposure to cisplatin is met (Strojan 2015, Szturz 2019). 
 
 
 
 
 
 
 
Therefore, the current study will evaluate if xevinapant with QW cisplatin (
mg/m2) and RT is 
safe and tolerable to use in the definitive LA SCCHN setting. 
Furthermore, in the current study, there is specific guidance for the management of renal 
impairment depending on grade of severity and first occurrence versus recurrence. (See Table 7). 
This includes dose modification of xevinapant, of cisplatin or a switch from cisplatin to an 
equivalent carboplatin dose (area under the concentration vs time curve [AUC] 
QW). This 
regimen is widely accepted and was reported to have similar efficacy (Wilkins 2013). 
No PK interactions between xevinapant at 
mg/day and cisplatin are expected based on data 
from Study Debio 1143-202 (cisplatin at 
mg/m2) and Study Debio 1143-201 (cisplatin at 
100 mg/m2) and consistent with the reported clearance mechanism of cisplatin. 
IMRT 
High-dose RT (60 to 72 Gy) is necessary to potentially cure patients with LA SCCHN. Irradiation 
of critical normal tissue can cause severe discomfort 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 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 LA 
SCCHN. In the curative setting, the recommended radiation dose is 70 Gy over 35 fractions 
(NCCN v1 2023, Machiels 2020). The dose should follow the International Commission on 
Radiation Units & Measurements recommendations and using IMRT with simultaneous integrated 
boost technique. 
4.4 
End of Study Definition  
The primary completion date is defined as the data cut-off date for the primary analysis when a 
total of 38 participants have completed the 5 weeks DLT-like assessment period or discontinued 
earlier and are not replaced. After the primary completion date, follow-up continues until the end 
of study defined below. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
43/154 
 
 
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 made 
or the last remaining on-study participant reaches their 18-month post-first treatment visit, 
whichever 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 they have completed all study parts, including the last 
visit or the last scheduled procedure shown in Section 1.3. Participants will receive the appropriate 
follow-up treatment per institutional standards. 
5 
Study Population  
The study will enroll unresected LA SCCHN participants who are eligible for cisplatin-based 
chemoradiotherapy. 
The criteria in Sections 5.1 and 5.2 are designed to enroll only individuals who are appropriate for 
the study; thereby, ensuring the study fulfills its objectives. All relevant medical and nonmedical 
conditions are considered when deciding whether an individual 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 individual’s routine medical care, 
the Investigator will confirm that the individual has provided written informed consent, as 
indicated in Appendix 5. 
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. Having an ECOG PS 0 - 1. 
 
3. Histologically confirmed diagnosis in previously untreated LA 
SCCHN patient (Stage III, IVA, or IVB according to the 
American Joint Committee on Cancer [AJCC]/TNM Staging 
System, 8th Ed.) suitable for definitive CRT, with one of the 
following primary sites: oropharynx (OPC) (HPV-negative), 
hypopharynx, and larynx. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
44/154 
 
 
Category 
Criterion 
 
4. Evaluable tumor burden (measurable and/or non-measurable 
tumor lesions) assessed by CT scan and/or MRI, based on 
RECIST v 1.1. 
 
5. For OPC patients, primary tumors must be HPV-negative as 
determined by p16 expression using immunohistochemistry 
(IHC) (pathological report should be available, p16 cutoff for 
determination of HPV status is defined in Section 8.2.4) 
Note: If the site is not able to perform HPV testing by p16 IHC, 
it will be evaluated by a central laboratory, except for countries 
where EU IVDR is applicable (see Section 8.2.4). 
 
6. Able to swallow liquids or has an adequately functioning feeding 
tube, gastrostomy, or jejunostomy in place. For participants 
requiring liquid nutrition at baseline or during the study 
including the follow-up period, access to liquid nutrition supply 
should be ensured. 
 
7. Peripheral neuropathy Grade < 2. 
 
8. Adequate hematologic, renal, and hepatic function as indicated 
by: 
• eGFR ≥ 60 mL/min/1.73 m² (using the CKD-EPI creatinine 
formula). 
• Absolute neutrophil count (ANC) ≥ 1,500 cells/μL. 
• Platelets ≥ 100,000 cells/μL. 
• Hemoglobin ≥ 9.0 g/dL (blood transfusions during screening 
are permitted). See also exclusion criteria #9. 
• Aspartate aminotransferase (AST) and alanine transaminase 
(ALT) ≤ 3.0 x upper limit of normal (ULN). 
• Total bilirubin ≤ 1.5 × ULN (up to 2.0 × ULN is allowed if 
the direct bilirubin level is normal and the elevation is 
limited to indirect bilirubin). 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
45/154 
 
 
Sex and 
Contraception/ 
Barrier Requirements 
9. Are of any sex and gender 
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. 
Male study participants: 
Agree to the following during the study intervention period and for 
6 months or according to local guidelines and/or local product 
information (whichever is longest), after the last administration of 
chemotherapy or 3 months after last dose of xevinapant whichever is 
the latest. 
• Refrain from donating fresh unwashed semen. 
PLUS, either: 
• Abstain from any activity that allows for exposure to ejaculate. 
OR 
• Use an external condom: 
o When having sexual intercourse with a partner of childbearing 
potential, who is not currently pregnant, and instruct the 
partner to use a highly effective contraceptive method with a 
failure rate of < 1% per year, as described in Appendix 6, 
since a condom may break or leak. 
o When engaging in any activity that allows for exposure to 
ejaculate. 
Female study participants: 
• Is not breastfeeding. 
• Is not pregnant (i.e. has a negative serum or highly sensitive urine 
pregnancy test, as required by local regulations, within 24 hours 
before the first dose of xevinapant). If a urine test cannot be 
confirmed as negative (e.g. an ambiguous result), a serum 
pregnancy test is required. 
• Is not a POCBP. 
• If a POCBP, 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 6 for the following time 
periods: 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
46/154 
 
 
Category 
Criterion 
1. Before the first dose of the xevinapant, if using hormonal 
contraception: 
• Has completed at least one 4-week cycle of an oral 
contraception pill and either had or has begun their menses; 
OR, 
• 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 
xevinapant is administered) for 6 months or according to local 
guidelines and/or local product information (whichever is 
longest) after the last administration of chemotherapy or 
3 months after last dose of xevinapant, whichever is the latest, 
and agree not to donate eggs (ova, oocytes) for reproduction 
during this period. 
The Investigator evaluates the effectiveness of the contraceptive 
method in relationship to the first dose of xevinapant. 
The Investigator reviews the medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a participant 
with an early undetected pregnancy. 
Informed Consent 
10. Are capable of giving signed informed consent, as indicated in 
Appendix 5, which includes compliance with the requirements 
and restrictions listed in the ICF and this protocol. 
 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Category 
Criterion 
Medical Conditions 
1. Primary tumor of nasopharyngeal, paranasal sinuses, nasal, or 
oral cavity, salivary, thyroid, or parathyroid gland pathologies, 
skin, or unknown primary site. 
2. Metastatic disease (Stage IVC as per AJCC/TNM, 8th Ed.). 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
47/154 
 
 
Category 
Criterion 
 
3. Existing need of a hearing aid 
OR 
≥ 25 decibel shift over 2 contiguous frequencies on a 
pretreatment hearing test as clinically indicated. 
 
4. Known history of infection with HIV. If unknown history of 
HIV, an HIV screening test is to be performed and participants 
with positive serology for HIV-1/2 must be excluded. 
 
5. Chronically active HBV or HCV infection. The following tests 
must be performed and participants with positive serology must 
be excluded (Section 8.2.4): 
• HBV screening tests: both HBsAg and HBcAb 
• HCV screening tests: both HCV-antibody and positive viral 
load HCV-RNA by PCR. 
 
6. 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. 
 
7. Known gastrointestinal disorder with clinically established 
malabsorption syndrome and major gastrointestinal surgery in 
the last 12 months that may limit oral absorption. 
 
8. Documented weight loss of > 10% during the last 4 weeks prior 
to the start of study intervention (unless adequate measures are 
undertaken for nutritional support), OR plasmatic albumin 
< 3.0 g/dL. No albumin transfusions are allowed within 2 weeks 
before the start of study intervention. 
 
9. 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 the 
start of study intervention. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
48/154 
 
 
Category 
Criterion 
 
10. Active inflammatory disease (including rheumatoid arthritis, 
systemic lupus erythematosus, Sjögren syndrome, severe 
extensive psoriasis, inflammatory bowel diseases, pneumonitis, 
and other autoimmune diseases) who are under antitumor 
necrosis factor treatment. 
 
11. 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 the start of study 
intervention. 
• 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 the start of study intervention. 
• 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 
start of study intervention. 
• Ongoing or known history of transient ischemic attacks or 
stroke within 6 months prior to the start of study intervention. 
• 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). 
 
12. History of another malignancy within last 3 years prior to start 
of study intervention, with the exception of 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. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
49/154 
 
 
Category 
Criterion 
 
13. Liver cirrhosis (Child-Pugh score: B or C). 
Prior/Concomitant 
Therapy 
14. Prior definitive, neoadjuvant, concurrent, or adjuvant (C)RT 
and/or radical surgery to the head and neck region which may 
jeopardize the primary tumor irradiation plan, or any other prior 
SCCHN systemic treatment, including investigational agents 
(please refer to Section 6.8) 
 
15. Use of the following: 
• Prohibited medication. These medications and time window 
to stop these medications prior to the start of study 
intervention are further specified in Section 6.8.3. 
• Treatment with an investigational agent or use of an 
investigational device within 4 weeks of the start of study 
intervention or during study intervention 
• Live attenuated vaccines within 28 days prior to start of study 
intervention. 
• Concurrent use of anticancer therapy 
• 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 study 
intervention. 
 
16. Patients with active immunodeficiency or patients receiving 
ongoing immunosuppressive therapy. 
 
17. Prior organ transplantation, including allogeneic stem cell 
transplantation. 
Prior/Concurrent 
Clinical Study 
Experience 
18. Participation in any interventional clinical study within 28 days 
prior to screening or during participation in this study. 
Diagnostic 
Assessments 
19. Known contraindication to undergoing positron emission 
tomography with 18F-FDG-PET scans or to both contrast-
enhanced MRI and contrast-enhanced CT scans. 
Other Exclusions 
20. Known allergy to xevinapant, cisplatin, carboplatin or any other 
platinum-based agent, or any excipient known to be present in 
the formulation of any of these products. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
50/154 
 
 
Category 
Criterion 
 
21. 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. 
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 
1 day after the final dose: Seville oranges, grapefruit or grapefruit juice, or grapefruit-containing 
products, St John’s Wort (i.e. Hypericum perforatum, millepertuis) and St John’s Wort-containing 
products because of the risk of DDIs with P-gp (Section 6.8.3). 
Xevinapant should be administered orally, early 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 
1 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. 
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 start of study intervention. Dental examination, audiometry, 
HBV/HCV/HIV test, fiberoptic endoscopy, and 18F-FDG-PET scan performed within 4 weeks 
before the last signed ICF do not have to be repeated during screening. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
51/154 
 
 
5.5 
Criteria for Temporarily Delaying 
Enrollment/Administration of Study Intervention  
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 overall design and timing of the treatments. 
 
 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
52/154 
 
 
Table 5 
Study Intervention(s)Administered  
Intervention Label 
Xevinapant 
Cisplatin 
Carboplatin (Only 
Used in Case of 
Cisplatin Toxicity 
as per Table 8) 
IMRT 
Intervention Name 
Xevinapant 
Cisplatin 
Carboplatin 
IMRT 
Intervention 
Description 
mg oral solution 
once daily for 14 
days of each 3-week 
cycle 
mg/m2 iv solution 
once weekly for 
7 weeks 
Carboplatin solution 
iv 
once per 
week 
(total platinum 
dosing should not 
exceed 7 weeks) 
70 Gy total radiation 
given in 35 fractions 
delivered 
5 days/week for 
7 weeks 
Type 
Drug 
Drug 
Drug 
Radiation 
Dose Formulation 
Oral solution 
Concentrate for 
solution for iv 
infusion 
Concentrate for 
solution for iv 
infusion 
NA 
Unit Dose 
Strength(s) 
 
 
 
 
Vial of 100 mL 
containing 100 mg 
cisplatin (1 mg/mL) 
if provided centrally 
by the Sponsor. The 
unit dose can differ 
if cisplatin is locally 
sourced. 
Vial of 15 mL 
containing 150 mg 
carboplatin 
(10 mg/mL) 
if provided centrally 
by the Sponsor. The 
unit dose can differ 
if carboplatin is 
locally sourced. 
NA 
Dose 
 mg 
mg/m2 
 
70 Gy 
Dosage Regimen 
Once daily 
Day 1 - 14 of a 
3-week cycle 
Once weekly for 
7 weeks 
Once weekly 
(total platinum 
dosing should not 
exceed 7 weeks) 
2 Gy once daily 
5 days/week for a 
total of 35 fractions 
Route of 
Administration 
Oral 
iv infusion 
iv infusion 
NA 
Use 
Experimental 
Background 
intervention 
Background 
intervention 
Background 
intervention 
IMP or NIMP/AxMP 
IMP 
IMP/AxMP, 
depending on local 
regulation 
IMP/AxMP, 
depending on local 
regulation 
NA 
Sourcing 
Provided centrally 
by the Sponsor 
Provided centrally 
by the Sponsor or 
locally by the study 
site,/CRO, or 
designee 
Provided centrally 
by the Sponsor or 
locally by the study 
site,/CRO, or 
designee 
NA 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
53/154 
 
 
Intervention Label 
Xevinapant 
Cisplatin 
Carboplatin (Only 
Used in Case of 
Cisplatin Toxicity 
as per Table 8) 
IMRT 
Packaging and 
Labeling 
Xevinapant will be 
provided in 
. 
 
and labeled 
per all applicable 
regulatory 
requirements and 
GMP guidelines. 
Depending on the 
local regulations, 
cisplatin may either 
be sourced from a 
local hospital 
pharmacy or 
supplied by the 
Sponsor (or 
designated service 
provider) and will be 
packaged/labeled 
per all applicable 
regulatory 
requirements and 
GMP guidelines. 
Depending on the 
local regulations, 
carboplatin may 
either be sourced 
from a local hospital 
pharmacy or 
supplied by the 
Sponsor (or 
designated service 
provider) and will be 
packaged/labeled 
per all applicable 
regulatory 
requirements and 
GMP guidelines. 
NA 
Former Name 
Debio 1143 
NA 
NA 
NA 
AUC=Area under the curve, AxMP=Auxiliary medicinal product, GMP=good manufacturing practice, 
IMP=Investigational medicinal product, IMRT=Intensity-modulated radiation therapy, iv=intravenous, NA=not 
applicable, NIMP=Noninvestigational medicinal product. 
Table 6 
Study Arm(s)  
Arm Name 
Single Arm study 
Combination Therapy: Xevinapant+ cisplatin + concomitant IMRT 
Monotherapy: Xevinapant  
Arm Type 
Experimental  
Arm Description 
Combination Therapy: Xevinapant, QD for 14 days, Q3W cycles, + cisplatin (
mg/m2) 
Day 2/week + concomitant IMRT 
Monotherapy: Xevinapant
mg QD for 14 days, Q3W cycles 
Associated 
Intervention Labels 
Xevinapant 
Cisplatin 
Carboplatin (Only used in case of Cisplatin Toxicity) 
IMRT 
IMRT: Intensity-modulated radiation therapy, QD: once a day, Q3W=Every 3 weeks 
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. 
CCI
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
54/154 
 
 
• 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, 
 and vial 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. 
6.3 
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding  
6.3.1 
Study Intervention Assignment  
Study Type 
 
Study using IRT 
After confirmation of participant’s eligibility and at the last 
practical moment prior to study intervention administration, 
participants will be centrally allocated to study intervention using 
an IRT and per a computer-generated list. 
The IRT will be used to assign unique participant numbers, allocate 
participants to study intervention at each study intervention visit. 
Before the study is initiated, the directions for the IRT will be 
provided to each site. The site will contact the IRT prior to starting 
study intervention administration for each participant. 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
55/154 
 
 
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 CRF. A member of the 
study site staff other than the person administering the study intervention will confirm the study 
intervention dose and study participant identification at the time of dosing. 
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 
regimen are recorded in the CRF. Participants will be instructed to return used and unused 
xevinapant 
 to the site to allow drug accountability by the medical staff. 
A record of the number of cisplatin or carboplatin vials administered to the participants and 
xevinapant 
 and 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 be recorded in the CRF. In 
addition, for each study intervention (xevinapant, cisplatin [or carboplatin in case of cisplatin 
toxicity], and IMRT) the reasons for dose modification, interruption, and discontinuation must be 
recorded in the CRF. 
6.5 
Dose Modification  
6.5.1 
Xevinapant Administration  
Xevinapant oral solution at 
mg/day will be administered once daily from Day 1 to Day 14 of 
a 3-week cycle, during 6 cycles (Table 2,  
Table 3, and Figure 3). Xevinapant should be administered orally, preferably in the morning. If 
necessary, the oral solution will be administered via a nasogastric tube, percutaneous endoscopic 
gastrostomy, or percutaneous endoscopic jejunostomy tube. 
If the participant forgets to take the scheduled dose of xevinapant more than 8 hours after the time 
of intake, then the participant should skip that dose. 
Xevinapant will be dispensed by the medical staff or Pharmacist of the investigational sites. The 
participant will receive xevinapant on an outpatient basis. 
On days of PK sampling at C1D2, C1D9, and C2D2, participants should take their doses at the 
hospital, where the administration of xevinapant will be supervised and recorded by the medical 
staff. The time of dose administration should be recorded in the eCRF and in the participant’s diary 
for all doses. 
The treatment schedule of xevinapant is presented in Figure 3, Table 2 and  
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
56/154 
 
 
Table 3. Participants will be instructed by the medical staff on how to self-administer xevinapant 
at home. The participant should inform the medical staff of any missed or delayed doses. In 
addition, a Participant Diary will be provided to participants to record xevinapant intakes at home. 
Please refer to Sections 6.4 and 8.2.6 for further details. 
6.5.1.1 
Concurrent Administration to Chemotherapy and IMRT  
 
 
 
On days when IMRT is to be administered without chemotherapy (see Table 2 and Section 6.5.3), 
xevinapant should be preferably administered before IMRT. 
If chemotherapy or IMRT are put on hold or discontinued, please refer to Section 6.5 to adapt 
xevinapant administration accordingly. 
6.5.1.2 
Dose Modification, Interruption, and Discontinuation of 
Xevinapant Treatment  
For participants who do not tolerate the study intervention, adjustments to the study intervention 
dose are permitted to allow the participant to continue on-study intervention according to the 
guidelines below. 
The guidelines for xevinapant dose modifications for toxicities considered at least possibly related 
to study intervention are outlined in Table 7 and Table 8, for combination therapy and 
monotherapy, respectively. 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. 
In case a dose reduction is necessary, the study intervention will be administered as follows: 
For each participant, a maximum of 2 dose reductions of xevinapant will be allowed during the 
study. 
The volume of the oral solution equivalent to each dose level is the following: 
• Planned dose (Level 0):  
 corresponds to 
mg/day of xevinapant 
• Dose Level 1: 
 corresponds to 
mg/day of xevinapant 
• Dose Level 2: 
 corresponds to 
mg/day of xevinapant 
General rules for xevinapant 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 
mg/day 
(
 of oral solution) per step will be allowed, down to a minimum dose of 
mg 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
57/154 
 
 
 of oral solution). If further dose reduction is required, the participant must be 
permanently discontinued from xevinapant administration (other ongoing treatments can 
continue, see Sections 6.5.2 and 6.5.3). 
• If the onset of several toxicities leads to conflicting recommendations as described in Table 7 
the most conservative dose adjustment among all toxicities presented must be followed. 
• No re-escalation of xevinapant dose after dose reduction will be allowed during the study. 
Once xevinapant dose has been reduced, participant will keep receiving the same dose until the 
EOT, or until further dose reduction or permanent treatment discontinuation, if required due to 
tolerability issues. 
• Xevinapant doses 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, xevinapant should be interrupted. If 
IMRT is restarted, xevinapant should be resumed at the next originally scheduled intake day of 
xevinapant, provided other rules of dose interruption are not met (see Section 6.5.3.3). If IMRT 
is permanently discontinued due to safety issues, then xevinapant administration should be 
maintained, and the participant can enter the monotherapy period. Otherwise, xevinapant 
treatment should be discontinued permanently, the EOT visit should be performed, and the 
participant should stay on study for follow-up as per protocol. IMRT may be interrupted for up 
to a maximum of 10 treatment days in total. 
• Monotherapy treatment period: If a participant requires a xevinapant dose interruption of more 
than 21 consecutive days due to study intervention-related toxicities, the Investigator should 
consider discontinuing the treatment. If a participant is discontinued from the monotherapy 
treatment, the EOT visit should be performed. Hereafter, the participant will continue with the 
study as per schedule and will enter the FU period. 
• Chemotherapy discontinuation will NOT result in xevinapant discontinuation. 
• Participants who prematurely discontinue from all treatments, i.e. chemotherapy, IMRT, and 
xevinapant, in the absence of disease progression will undergo the EOT visit and then enter the 
follow-up period according to schedule. 
• Any dose modification and dose interruption including the reason must be recorded on the 
Dosage Administration Record eCRF. 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
58/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
59/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
60/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
61/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
62/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
63/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
64/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
65/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
66/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
67/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
68/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
69/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
70/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
71/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
72/154 
 
 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
73/154 
 
 
6.5.1.3 
End of Xevinapant Treatment  
Xevinapant treatment will be administered until the 6 cycles of therapy (i.e. 3 cycles of 
combination therapy followed by 3 cycles of monotherapy) are completed or until any of the study 
intervention discontinuation criteria described in Section 7.1 occur. 
Note: If IMRT is permanently discontinued due to severe or intolerable toxicities as per 
Investigator’s discretion, then the participant can enter the monotherapy period. 
Discontinuation from study 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. 
6.5.2 
Chemotherapy  
All participants will receive cisplatin (
mg/m2) intravenously over at least 90 minutes on Day 2 
QW up to a maximum of 7 cycles in total (see administration schedule in Table 2). If body surface 
area is > 2.00 m2, the maximum dose per infusion will be capped at a maximum of 80 mg. 
A total cumulative cisplatin dose of 
mg/m2 is recommended (Machiels 2020), based on 
various studies suggesting a sufficient therapeutic effect when this exposure to cisplatin is met 
(Strojan 2015, Szturz 2019) Please consult and follow cisplatin administration instructions 
provided in your local label and institutional guidelines. The infusion has to be administered with 
pre- and postinfusion hydration ± mannitol and/or diuretics. Any pre-existing dehydration should 
be corrected. Please refer to Appendix 3 and Appendix 4 for additional information on cisplatin 
administration and hydration regimen respectively. 
 
 
 
eGFR (using the CKD-EPI creatinine formula) should be ≥ 60 mL/min/1.73 m2 before 
administration of cisplatin at C1D2; retreatment conditions as specified in Table 7 should be met. 
Participants should receive at least 1 full cisplatin infusion, such as on C1D2, before dose 
reduction, or switch to carboplatin. 
Standard antiemetic prophylaxis for cisplatin containing regimens is mandatory starting on Day 1 
of each chemotherapy containing cycle. Standard antiemetics guidelines (administration of pre- 
and post-treatment serotonin receptor antagonists, neurokinin-1 receptor antagonists and 
dexamethasone [or any other corticosteroid at equivalent dose iv] according to the 2016 MASCC 
and ESMO guideline (Roila 2016) are provided in Section 6.8.1.1; however, the specifics of the 
regimen are at the discretion of the treating physician, provided adequate control is achieved. 
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
74/154 
 
 
Note: Please refer to Section 6.8.1.1 for the proposed adjusted dosage/schedule for dexamethasone 
and aprepitant due to perpetrator drug-drug interaction potential of xevinapant via inhibition of 
CYP3A4. 
A participant not eligible to continue with QW cisplatin after dose reduction can switch to 
carboplatin as per the dose modifications outlined in Table 7 (NCCN Chemotherapy Order 
Templates 2020). Please consult and follow the carboplatin administration instructions provided 
in your local label. 
No pre- or post-treatment hydration or forced diuresis is required for carboplatin administration. 
6.5.2.1 
Dose Modification, Interruption, and Discontinuation of 
Chemotherapy  
Permitted cisplatin dose levels: 
• Planned dose (level 0): corresponds to cisplatin 
mg/m2 
• Dose level - 1: corresponds to cisplatin 
mg/m2 
 
• Dose level - 2: corresponds to cisplatin 
mg/m2 
 
For participants switching to carboplatin: carboplatin AUC = 2 mg·min/mL is allowed. 
Please refer to Table 7 for instructions on dose modifications, interruption, discontinuation of 
chemotherapy, and potential switch to carboplatin in case of toxicity suspected to be related to 
study intervention. 
Toxicity related to chemotherapy administration includes but is not limited to nausea, vomiting, 
renal toxicity (with an elevation of blood urea nitrogen and creatinine and impairment of 
endogenous creatinine clearance, as well as renal tubular damage, which appears to be transient), 
peripheral neuropathy, ototoxicity (with hearing loss that initially is in the high-frequency range, 
as well as tinnitus), and hyperuricemia. Much more severe and prolonged toxicity has been 
observed in participants with abnormal or obstructed urinary excretory tracts. Myelosuppression, 
often with delayed anemia, is expected. 
Chemotherapy dose adjustments at the start of a cycle should be based on the nadir of hematologic 
counts or maximum nonhematologic toxicity from the previous treatment cycle. Chemotherapy 
infusion may be delayed to allow for sufficient recovery time. 
6.5.2.2 
End of Chemotherapy  
Chemotherapy will be administered until completion of the 7 weekly infusions of platinum-based 
therapy planned in the study or until any of the study intervention discontinuation criteria described 
in Section 7.1 occur. 
Note: Chemotherapy discontinuation will not automatically have to result in xevinapant 
discontinuation or IMRT discontinuation 
CCI
CCI
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
75/154 
 
 
Dose modifications, treatment interruption, switching from cisplatin to carboplatin, and permanent 
discontinuation of any of the components of the study intervention is to be recorded in the Dosing 
CRF of each component of the study intervention. For each action, the reason must be recorded. 
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. 
6.5.3 
Radiotherapy  
6.5.3.1 
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 nutrition 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. 
6.5.3.2 
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 5) 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 Manual). 
The IMRT plan must be reviewed by the RT-QA Review Center prior to the start of the IMRT. A 
summary of radiotherapy requirements and recommendations is described below. 
 
 
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. 
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. 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
77/154 
 
 
6.5.3.3 
Treatment Interruption  
IMRT interruption is strongly discouraged, and every attempt should be made to keep the treatment 
continuous and adhere to the overall treatment time as prescribed (7 weeks). Planned radiotherapy 
interruptions are not allowed. Any interruption must be clearly indicated in the treatment record 
and reasons should be documented. 
IMRT may be interrupted for up to a maximum of 10 treatment days in total to allow 
resolution/improvement of radio-chemo toxicities such as Grade 4 mucositis measured by physical 
or functional examination, or Grade 4 radiodermatitis (see Section 6.5.3.4 for management of those 
toxicities). 
Treatment interruption due to a nonmedical reason should be minimized as much as possible and 
should not exceed 2 consecutive treatment days per interruption (Radiologists 2019). In case of 
interruption for technical reasons (e.g. malfunction or revision of the treatment machine), 
continued treatment must be ensured, and the use of another unit is recommended. For units that 
have different energy levels, it is recommended to perform the dosimetry on an alternative device. 
If a fraction has to be compensated, it can be administered after the planned 35 fractionation days 
(Cycle 1 to 3) or it can be compensated during the 35 fractionation days. If compensated during 
the 35 fractionation days, the fractions should be at least 6 hours apart. Xevinapant administration 
should not be compensated. In any case, there must be no more than 5 days of treatment in a given 
week. 
If IMRT is permanently discontinued due to severe and intolerable toxicities as per Investigator’s 
judgment, then xevinapant monotherapy administration should be maintained, and the participant 
can enter the monotherapy period. 
6.5.3.4 
Management of Acute “in Radiation Field” Toxicity  
If dermatitis, mucositis, or dysphagia occurs, the possibility of IMRT interruption should be 
assessed according to their severity. Institutional guidelines on prophylaxis and dental hygiene will 
be followed for management of skin and mucosal toxicity. 
For any other degree of minor toxicity, the necessary support measures must be taken to ensure 
treatment continuity (Peterson 2015). 
In the event of mucositis, the following recommendations will be considered: 
• Rapid escalation of analgesics using the World Health Organization cancer pain relief ladder 
(WHO 2018). 
• Enteral or parenteral nutritional support according to the institutional guideline. Enteral 
nutritional support is strongly recommended if weight loss is ≥ 5%. If the weight loss is ≥ 10%, 
the use of a nasogastric or gastrostomy tube must be implemented as quickly as possible 
(Elad 2019) and access to adequate nutritional support needs to be secured by the Investigator. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
78/154 
 
 
The management of radiation dermatitis should be based on the severity of symptoms, as 
determined by Radiation Therapy Oncology Group and should follow the recommendations by the 
Supportive Care Guidelines Group. 
6.5.3.5 
End of Radiotherapy  
Radiotherapy will be administered until completion of the IMRT dose and schedule (see Table 9) 
planned in the study or until any of the study intervention discontinuation criteria described in 
Section 7.1 occur. 
Note: Radiotherapy discontinuation will not result in xevinapant discontinuation or chemotherapy 
discontinuation. See further Section 6.5.1.3. 
Treatment interruption and permanent discontinuation of any of the components of the study 
intervention is to be recorded in the Dosing CRF of each component of the study intervention. For 
each action, the reason must be recorded. 
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 
mg/day and/or xevinapant intake exceeding 
14 days per cycle, any dose of cisplatin higher than 
mg/m2 per cycle, or any dose of carboplatin 
higher than AUC 
 per cycle, will be considered an overdose. 
The Sponsor has no specific recommendation for treating an overdose. The Investigator will use 
their clinical judgment to manage any overdose, considering the symptoms, and any site 
procedures or standards. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the participant should be observed closely for signs of toxicity. 
Even if not associated with an AE or SAE, any overdose is recorded in the CRF and reported to 
global patient safety in an expedited manner. Overdoses are reported on an SAE and Overdose 
Report Form, following the procedure in Appendix 7. 
6.8 
Concomitant Therapy  
Record in the CRF all concomitant therapies (e.g. medicines or nondrug interventions) used from 
the signing of the ICF until the EOS visit at the timepoints specified in the SoA (Section 1.3), 
including any changes. For prescription and over-the-counter medicines, vaccines, vitamins, and 
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
79/154 
 
 
herbal supplements, record the name, reason for use, dates administered, and dosing information. 
For nondrug interventions, record the name, and dates administered. 
Contact the Medical Monitor for any questions on concomitant or prior therapy. 
6.8.1 
Permitted Medicines  
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. 
• Investigators will assess prior to, or at the beginning of the screening period, whether a 
participant will be vaccinated against a specific infectious disease (e.g. COVID-19 or mpox 
infection) that may be a significant risk to the participant during the study before receiving the 
first dose of study intervention. 
In general, Investigators will consider that the vaccination effect may be reduced in participants 
with cancer and may not lead to protection depending on the extent of the immunocompromised 
state of the participant, including the impact of prior therapies. 
6.8.1.1 
Antiemetics  
The specific antiemetic regimen is at the discretion of the Investigator, provided adequate control 
is achieved. Related information should be reported in the eCRF. For participant receiving 
cisplatin, antiemetic therapy including dexamethasone (or any other corticosteroid at equivalent 
dose iv.), 5-HT3 serotonin receptor antagonists and neurokinin-1 receptor antagonists can be 
administered as per 2016 MASCC and ESMO guideline (Roila 2016). However, dosage/schedule 
adjustment for both the dexamethasone and aprepitant should be considered, due to elevated 
plasma concentrations of these drugs fold triggered by xevinapant inhibition of CYP3A4. Strong 
CYP3A4 inhibitors increased AUC of dexamethasone ~ 3-4 fold and AUC of aprepitant ~ 5 fold, 
respectively. 
For instance, the Investigator can consider the following regimen: 
Day of cisplatin administration (Day 1 of cisplatin = Day 2 of each treatment cycle): 
• 5-HT3 serotonin receptor antagonists iv., at the appropriate antiemetic dose for highly 
emetogenic regimens. If ondansetron is used with xevinapant, participant should be 
monitored closely (see also Section 6.5.2). Alternative 5-HT3 serotonin receptor antagonists 
should be used, if possible. 
• Dexamethasone: 8 mg or any other corticosteroid at an equivalent dose orally (to be taken 30 
minutes prior to chemotherapy). 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
80/154 
 
 
• Aprepitant: oral 125 mg at least 30 minutes prior to infusion. 
Day 2 after cisplatin administration: Dexamethasone 4 mg + aprepitant 80 mg/day ± 5-HT3 
serotonin receptor antagonist 
Day 3 after cisplatin administration: Dexamethasone 4 mg ± 5-HT3 serotonin receptor antagonist 
For participants receiving carboplatin, antiemetic therapy including dexamethasone (or any other 
corticosteroid at an equivalent dose iv.) and 5-HT3 serotonin receptor antagonists may be 
administered as per 2016 MASCC and ESMO guideline (Roila 2016). If dexamethasone is used, 
the modified dosage/schedule described above for cisplatin could also be considered. 
Note: Dose and schedule of dexamethasone coupled with its wide availability in various forms 
established it as the agent of choice in the 2016 MASCC and ESMO guidelines. If an equivalent 
dose of corticosteroids is used according to institutional guidelines, the risk of increased toxicity 
to corticosteroids should be carefully monitored. Elevations of plasma levels may be triggered by 
xevinapant inhibition of CYP3A4 as described above for dexamethasone. 
6.8.2 
Medications to be Used with Caution With Xevinapant  
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 are recommended 
to be used under close medical monitoring. Some CYP3A substrates (not prohibited as per 
Section 6.8.3.1) 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 or transported by P-gp, refer to the recommendations 
of the product information. 
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 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
81/154 
 
 
• 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 
 
Prevacid 
Lansoprazole 
Clopidogrel 
Ondansetron (allowed alternative: dolasetron, granisetron, tropisetron, 
palonosetron) 
Colchicine 
Posaconazole (systemic) 
Dabigatran 
Riociguat 
Digoxin 
Valproic Acid 
The metabolism and transport of the above listed drugs occurs through CYP3A4/5 and/or P-gp. 
As per their product information, the clinical relevance of their coadministration 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 
coadministered 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. 
6.8.3 
Prohibited Medicines  
6.8.3.1 
Prohibited Medications with Xevinapant  
• 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 study intervention start or requirement for ongoing treatment with 
any drug(s) on the prohibited medication list in Sections 6.8.3.1.1, 6.8.3.1.2, 6.8.3.1.3, and 
6.8.3.1.5 or within 3 days prior to study intervention start for the drugs in Section 6.8.3.1.4 is 
an exclusion criterion. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
82/154 
 
 
• Treatment with an investigational agent other than xevinapant or use of an investigational 
device within 4 weeks of the first dose of study intervention or during study intervention. 
• In case of unavoidable concomitant administration of a prohibited medicine during 
investigational treatment, the need for suspension or discontinuation of xevinapant must be 
discussed beforehand with the Sponsor. 
• Live vaccines within 28 days prior to the start 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, bacille Calmette-Guerin, 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. 
6.8.3.1.1 
Recombinant Human Erythropoietin and Derivates  
Recombinant human erythropoietin (EPO) is not allowed throughout the entire duration of the 
study. 
Preclinical and clinical studies showed that autocrine or paracrine erythropoietin signaling can 
enhance cancer invasion in SCCHN and negatively affects patient outcome in terms of OS and 
local-regional PFS (Henke 2003, Lambin 2009). 
6.8.3.1.2 
Food and Herbal Preparations  
• Grapefruit juice and grapefruit-containing products (P-gp inhibitors) may lead to increased 
xevinapant exposure. 
• St John’s Wort (i.e Hypericum perforatum, millepertuis) and St John’s Wort-containing 
products (P-gp inducers) may lead to decreased xevinapant exposure. 
6.8.3.1.3 
Inhibitors/Inducers of P-gp  
The concomitant intake of strong inhibitors/inducers of P-gp is prohibited because they may have 
an impact on the PK disposition of xevinapant (i.e. increase the xevinapant exposure for inhibitors 
and decrease the xevinapant exposure for inducers). Commonly used drugs are listed below 
(Table 12). Please note that this is not an exhaustive listing; refer to the label of potential 
comedications to verify they are not strong inhibitors/inducers of P-gp. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
84/154 
 
 
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). 
6.8.3.1.5 
Prohibited or Concomitant Use of Traditional Chinese 
Medicines  
Any traditional Chinese medication with approval for use as anticancer treatment (regardless of 
the type of cancer) will not be permitted during study intervention. Traditional Chinese medicines 
for indications other than anticancer treatment, such as supportive care, may be administered at 
the discretion of the Investigator. Any traditional Chinese medicines or herbal supplement, if 
known to be strong inhibitors/inducers of CYP3A4 or inhibitors of P-gp, will not be permitted. 
Use of traditional Chinese medicines as part of next line of anticancer treatment should be 
documented as such. 
6.8.3.2 
Prohibited Medications and Medications to be Used with 
Caution with Cisplatin or Carboplatin  
Prohibited medications 
Platinum-based cytotoxic agents may reduce the digestive absorption of phenytoin and 
fosphenytoin, resulting in reduced epilepsy control and risk of exacerbation of convulsions. 
Therefore, both phenytoin, and fosphenytoin are prohibited during the combination therapy period. 
Granulocyte-Colony Stimulating Factors (G-CSF) are not allowed throughout the screening period 
and for prophylaxis. Nevertheless, for participants presenting with febrile neutropenia who have 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
85/154 
 
 
risk factors for infection-related complications or poor clinical outcome, therapeutic G-CSF 
including secondary prophylaxis should be considered (Becker 2020). Features associated with 
poor outcome include age > 65 years; sepsis syndrome; ANC < 100 neutrophils/m3; anticipated 
prolonged (> 10 days) neutropenia, pneumonia, or other clinically documented infection; invasive 
fungal infections; and hospitalization at the time of fever. 
Please also refer to the local product information for cisplatin or carboplatin, as applicable. 
Medications to be used with caution 
Please consult and follow the instructions provided in your local label. 
6.8.4 
Other Interventions  
6.8.4.1 
Nutritional Support  
All participants must be screened for nutritional risk and need of early enteral nutrition. Nutrition 
status must be evaluated as indicated in Table 1, Table 2, and  
Table 3. 
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. 
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 v1 2023). 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. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
86/154 
 
 
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  
Discontinuation of specific sites or of the entire study is specified in Appendix 5. 
7.1 
Discontinuation of Study Intervention  
Study intervention (i.e. xevinapant, cisplatin, and IMRT) must be discontinued under the following 
circumstances: 
• Disease progression, including clinical progression as judged by the Investigator, treatment 
failure, local, or distant relapse, second cancers, or start of any new anticancer treatment 
including salvage surgery. 
• 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 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). 
• Investigator decision in the participant’s best interest. The primary reason for this decision (e.g. 
lack of efficacy, AE) must be recorded in the eCRF. 
• Early study termination by the Sponsor, SMC, 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. The SoA indicates data to be collected at the time of 
discontinuation of study intervention and follow-up and for any further evaluations that need to be 
completed ( 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
87/154 
 
 
Table 3- EOT visit). 
7.1.3 
Temporary Discontinuation  
See Section 6.5.1.2 (xevinapant), Section 6.5.2.1 (cisplatin), and Section 6.5.3.3 (RT) for further 
guidance on temporary discontinuation of treatment. 
7.1.4 
Rechallenge  
See Section 6.5.1.2 for details on study intervention restart or rechallenge criteria. 
7.1.4.1 
Study Intervention Restart or Rechallenge After Liver 
Stopping Criteria Are Met  
Study intervention restart or rechallenge after liver clinical safety laboratory test stopping criteria 
are met by any participant in this study are not allowed. 
7.2 
Participant Discontinuation/Withdrawal from the Study  
• A participant may discontinue from the study at any time, at their own request or at the 
discretion of the Investigator for safety, behavioral, compliance, or administrative reasons (e.g. 
disruption of operations due to natural disasters, interruption of laboratory, or facility 
accreditation, participant moving to another country, resignation of key staff”). 
• 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. 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
88/154 
 
 
• 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. 
• If a participant requests the destruction of any biological samples still remaining, the 
Investigator will document this in the site study records and inform the Sponsor. The samples 
will be destroyed. 
• 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 with the participant until the AE is resolved. 
• Premature discontinuation from the study can also be triggered by: 
o Participant lost to follow-up (Section 7.3) 
o Death 
o Disease progression 
o Early study termination by the Sponsor, SMC, 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, for reasons other than DLT-like events earlier than 
5 weeks after start of treatment, may be replaced. 
7.3 
Lost to Follow-Up  
A participant will be considered lost to follow-up if repeatedly failing 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 will 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”. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
89/154 
 
 
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. 
• 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 will 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. 
• 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 5. 
• Procedures conducted as part of the participant’s routine medical care and obtained before 
signing of the ICF may be used for screening or baseline purposes provided the procedures met 
the protocol-specified criteria, were performed within the time frame defined in the SoA, and 
if reviewed, and approved by the Sponsor. 
• A participant will be allowed to receive study intervention 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 5). The IMRT plan must have been reviewed by the RT-QA Review Center prior 
to the start of the IMRT. 
• About 250 mL of blood total will be taken throughout the study. Up to 50 mL of blood may be 
drawn at certain visits. These blood samples will be used for the following purposes: clinical 
laboratory tests, PK, 
. The volume of collected blood might 
increase due to repeat collections that may be necessary. 
• 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. 
Order of Assessments 
• ECG readings must be taken prior to blood collection. 
Screening Period 
Participants will be screened between Days -28 and -1, prior to start of study intervention (Day 1 
[-3 days]). Activities and procedures to be performed at Screening are detailed in the SoA 
(Section 1.3). Screening-specific procedures include: 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
90/154 
 
 
• Demography: birth year, age at informed consent, sex, race (only where allowed by local 
law/regulations), and ethnicity. 
• Medical history: previous illness and surgeries (e.g. all during the past year and only major ones 
prior to that), concomitant illness, relevant medication/ therapies, allergies, tobacco use, alcohol 
use. 
• 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). 
• Disease history and tumor staging (using the AJCC/TNM Staging System, 8th Ed.) based on 
radiological imaging. Please refer to Section 8.1.1 for further details on radiologic imaging. 
• Results from the local laboratory should be used for defining participant eligibility during 
Screening. 
• Dental examination, audiometry (if required), HBV/HCV/HIV tests, fiberoptic endoscopy and 
18F-FDG-PET scan performed within 4 weeks before ICF signature do not have to be repeated 
during screening. 
• Intravenous 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 study intervention starts. 
• HPV status by p16 IHC (mandatory for OPC, optional for other tumor locations) does not have 
to be repeated if performed prior to ICF signature in line with instructions in Section 8.2.4.1. 
8.1 
Efficacy Assessments and Procedures  
Assessment of tumor response to treatment will be assessed locally according to the Response 
Evaluation Criteria in Solid Tumors (RECIST v1.1) as described in Appendix 2 but will also take 
into consideration clinical, anatomopathological, and functional assessments of the tumor. 
Tumor assessments (clinical and radiological) should be continued until disease progression (as 
per RECIST v1.1) occurs, next line of anticancer treatment is started, or EOS, whichever occurs 
first as per SoAs (Table 1, Table 2, and  
Table 3) and are scheduled, after the EOT visit, every 3 months. 
Participants who progress (as per RECIST v1.1) or who start next line of anticancer treatment will 
discontinue the study. If study intervention is permanently discontinued in participants without 
disease progression according to RECIST v1.1 (e.g. unacceptable toxicity), the participant will 
remain in the study to be evaluated for safety and efficacy. The SoA indicates data to be collected 
at the time of discontinuation of study intervention and follow-up and for any further evaluations 
that need to be completed ( 
Table 3-EOT visit). Efficacy assessments will continue to be performed until disease progression, 
start of next line therapy, or EOS, whichever occurs first. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
91/154 
 
 
8.1.1 
Radiological Assessment  
For each participant, the same radiological method for head and neck and for chest must be used 
throughout the study. The schedule of collection of iv contrast-enhanced CT scan or MRI of head 
and neck (which cover the orbits), CT scan of the chest, and 18F-FDG-PET/scan (from the skull 
base to the proximal upper legs) is provided in Table 1, Table 2, and  
Table 3. 
18F-FDG-PET scan is preferred to facilitate pre-and posttreatment evaluation of metabolic 
response and the need for posttreatment neck dissection. If physical examination and imaging 
suggest residual disease at the primary site at EOT, a biopsy should be performed whenever 
possible to confirm residual disease; otherwise, participants will undergo serial follow-up. 
Additional imaging assessments may be performed at any time during the study at the 
Investigator’s discretion to support the efficacy evaluations for a participant. Clinical progressive 
disease (PD) is recommended to be confirmed by imaging and/or endoscopy (i.e. biopsy). 
If an off-schedule imaging assessment is performed because progression is suspected, subsequent 
assessments should be performed in accordance with the original imaging schedule. 
Measurability of the Tumor at Baseline 
At baseline, participants may be included with measurable disease or with only evaluable, 
non -measurable disease according to RECIST v1.1 and as assessed by the Investigator. 
Measurable disease is defined as the presence and selection of at least 1 measurable nodal or 
non-nodal lesion. The assessment of participants at baseline according to RECIST v1.1 is covered 
in Appendix 2. 
Non-measurable disease means that only non-measurable lesions exist at baseline. Guidance on 
how participants with only non-measurable disease at Baseline will be evaluated for complete 
response and progression based on RECIST v1.1 is also defined in Appendix 2. 
Images may be collected retrospectively from the investigational sites in case it is later determined 
that an independent read is appropriate. 
8.1.2 
Radiological/Clinical Assessment at EOT and Follow-up 
All participants will be assessed at the EOT visit (20 [± 1] weeks) with clinical/radiological 
examinations as follows: 
• 18F-FDG-PET or 18F-FDG-PET/CT scans for determining the overall clinical outcomes and the 
need for nodal dissection (18F-FDG-PET should be ordered before examination under 
anesthesia with endoscopy, biopsies, and tonsillectomy, to help identify potential primary sites 
before any intervention occurs). 
• Ear, nose, and throat, and fiberoptic endoscopy. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
92/154 
 
 
These clinical assessments are to be performed according to the schedule presented in Table 1, 
Table 2, and  
Table 3. 
If the EOT scan was positive AND the participant underwent salvage surgery and END, no further 
18F-FDG-PET scans should be performed. If EOT results were inconclusive AND the participant 
did not undergo salvage surgery and END, the 18F-FDG-PET scan should be repeated 12 weeks 
after EOT (Week 31 ± 2 weeks). 
Clinical PD must be verified by imaging and/or biopsy, wherever possible. The presence or 
absence of residual viable tumor cells will be determined via a histopathological examination. 
Negative 18F-FDG-PET scan at Baseline, with a positive 18F-FDG-PET scan at EOT is a sign of 
PD based on a new lesion if considered related to the disease under study (a confirmatory biopsy 
should be performed whenever possible). Further details of the interpretation of 18F-FDG-PET 
scan in this study are supplied in Appendix 2. 
In case of doubt of a clinical local-regional recurrence or distant metastasis before the EOT, 
imaging by CT/MRI scan should be performed to verify disease progression. 
During the follow-up period the participants will undergo ear, nose, and throat examination, 
fiberoptic endoscopy as per institutional guidelines, and MRI and/or CT as per the schedule CT as 
per the schedule presented in  
Table 3. 
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, and will be done at screening and EOT. 
• A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver, spleen, and pancreas) as well as the head, mouth, 
and neck area, and will be done during treatment and follow-up visits. 
• Investigators will pay special attention to clinical signs related to previous serious illnesses. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
93/154 
 
 
8.2.2 
Vital Signs  
• Blood pressure and participant’s position during measurement; pulse; respiratory rate; 
temperature and location of measurement, weight, and height (at Screening only) will be 
measured and recorded. 
• 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. 
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 14. 
Table 14 
ECG Collection Plan  
Study Visit or Cycle 
Day 
Time Relevant to Dosing 
Screening 
-28 to -1 
NA 
Cycle 1 
1 
predosea 
0.5-4 hours postdose 
Cycle 1 
8 
predosea 
0.5-4 hours postdose 
ECG=electrocardiogram, NA=not applicable. 
a 
To be performed prior to all predose blood collection. 
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. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
94/154 
 
 
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 7 and Table 8): 
• 
 
• 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. 
• 
. 
• The participant will be referred to a cardiologist. 
• The Medical Monitor will be consulted prior to administering further xevinapant doses. 
• 
 
 
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 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. 
• 
 
• The participant will be referred to a local cardiologist. 
8.2.4 
Clinical Safety Laboratory Tests  
• Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 8 
at the timepoints 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, if applicable). Additional coagulation tests may have 
to be performed according to local practice. 
• Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will be 
conducted according to the schedule in Table 1, Table 2, and,  
• Table 3. 
o 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. 
CCI
CCI
CCI
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
95/154 
 
 
• 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 the local laboratory. For HPV testing, see additional instructions 
in Section 8.2.4.1. 
• 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 7. The laboratory reports will be filed with the source 
documents. 
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]. 
• p16 IHC results obtained prior to the participant’s consent to participation in the study are 
acceptable, pathological report should be available. 
o If the report is not available for HPV status by p16 IHC, for countries where EU IVD 
Regulation (IVDR) is applicable, only local lab testing on an 
 is 
allowed. 
o For countries not falling under the EU IVD Regulation (IVDR), the assessment can be done 
locally 
. If the site is not able to perform HPV testing by 
p16 IHC, it will be evaluated by a central laboratory. 
• 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 
Safety Monitoring Committee (SMC)  
The SMC will perform a safety review after 6, 12, 18, and 38 participants have been treated for at 
least 5 weeks or have experienced a DLT-like event. For the SMC review after 18 participants the 
tolerability of treatment will be assessed using the DLT-like criteria (Section 8.2.5.1) during the 
initial 5 weeks for each participant (DLT-like assessment period). Additional SMC reviews may 
be requested by the Sponsor or SMC. In addition, the SMC will decide upon stopping of the study: 
• In case of unacceptable toxicity 
• In case of treatment related death without possible alternative causality. 
For further details, see Section 9.2 and Appendix 5. 
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
96/154 
 
 
8.2.5.1 
Definition of DLT-like Events  
DLT-like events are defined as any of the following laboratory abnormalities or treatment-related 
AEs occurring during the DLT-like assessment period of 5 weeks that are assessed as related to 
study intervention: 
• Asymptomatic CTCAE Grade 4 neutropenia that persists > 7 days 
• CTCAE Grade ≥ 3 febrile neutropenia 
• Grade 4 Thrombocytopenia without bleeding lasting ≥ 5 days or Grade ≥ 3 thrombocytopenia 
with bleeding or requiring platelet transfusion. 
• CTCAE Grade ≥ 3 nonhematologic toxicity, including but not limited to: 
o 
 
o CTCAE Grade 4 dermal toxicity or mucositis if it interferes with study intervention 
delivery. 
• A dose of less than 60% of the planned cumulative dose of xevinapant or cisplatin in the 
respective treatment cycle due to treatment-related AE occurring during the DLT-like 
assessment period. 
Note: If dose reduction at the start of a next treatment cycle of xevinapant /cisplatin/carboplatin 
is required according to dose modification guidelines (Section 6.5.1.2), it is considered as a 
new planned dose. 
• RT delay > 2 weeks due to a treatment-related AE occurring during the DLT-like assessment 
period 
• CTCAE Grade 2 or higher ototoxicity worsening by 2 grades or more from baseline if deemed 
treatment limiting by the investigator 
• Any occurrence of drug-induced liver injury (DILI) meeting the Hy’s law criteria (i.e. defined 
as aminotransferases > 3 × ULN, alkaline phosphatase < 2 × ULN, total bilirubin ≥ 2 × ULN, 
with no other reason to account for these abnormalities) 
• CTCAE Grade ≥ 3 laboratory abnormalities 
• Any other life-threatening toxicity 
• Grade 5 toxicity 
Exceptions: 
1. Grade 3/4 nausea, vomiting, and diarrhea will be considered DLT-like events only if they 
persist for at least Grade 3 for > 3 days despite optimal therapy. Grade ≥ 3 fatigue and anorexia 
will not be considered DLT-like events 
2. Common CRT-related Grade 3 toxicities including laryngeal inflammation, skin reaction, 
dysphagia, oral dysesthesia, mucositis, mucosal infection, skin infection, oropharyngeal pain, 
laryngitis, pharyngitis, decreased appetite, salivary duct inflammation, radiation recall reaction, 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
97/154 
 
 
and xerostomia will not be considered DLT-like events unless if it leads to permanent 
discontinuation of treatment as assessed by the investigator. 
3. CTCAE Grade ≥ 3 lab abnormalities that are not interfering with study intervention delivery 
according to investigator assessment will not be considered DLT-like events. 
4. Grade ≥ 3 or higher electrolyte abnormality that lasts up to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical interventions. 
5. Grade 3 amylase or lipase that is not associated with symptoms or clinical manifestations of 
pancreatitis. 
6. Amylase increases originating from the salivary gland will also not be considered DLT-like 
events. 
The SMC will confirm any DLT-like event. 
8.2.6 
Patient Diary  
Xevinapant will be dispensed by the medical staff or pharmacist of the investigational sites. The 
participant will receive xevinapant on an outpatient basis. 
On days of PK sampling, C1D2, C1D9, and C2D2 participants must take their doses at the hospital, 
where the administration of xevinapant 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 prior to xevinapant PK 
collection (i.e. at C1D1, C1D8, C2D1) needs to be recorded in the participant’s diary, if taken at 
home, and all need to reported in the eCRF. 
The treatment schedule of xevinapant is presented in Table 2 and  
Table 3. Participants will be instructed by the medical staff on how to self-administer xevinapant 
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 2. 
They will be instructed on how to record xevinapant administration (i.e. date and time of the 
xevinapant intake should be recorded in the diary). 
Participant should record any skipped or miss-timed doses in their diary. 
Participants will be asked to bring the diary with them to their study visits. The diary will be 
collected and reviewed by site staff after the completion of each visit. 
8.2.7 
Audiometry  
An audiometry must be performed at screening. In addition, hearing clinical evaluation and 
audiometry should be performed if clinically indicated at C1D8, C1D15, C2D1, C2D8, C2D15, 
C3D1, and at any time as per institutional or national guidelines. During the follow-up period, an 
audiometry is to be performed only if clinically indicated, as per institutional or national 
guidelines. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
98/154 
 
 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting  
• The definitions of an AE and SAE are in Appendix 7. 
• The Investigator and any qualified designees (e.g. Subinvestigators) 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 AEs, considered related to the study 
intervention or study procedures, or that caused the participant to discontinue the study 
intervention or study, 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 7 
• All AEs and SAEs will be collected from the signing of the ICF until the EOS/follow-up visit 
at the timepoints specified in the SoA (Section 1.3). 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 7. 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. 
• 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 their 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 7. 
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. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
99/154 
 
 
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 7 
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 7. 
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 toward 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 Subinvestigator 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 read it and confirm completion of this activity. 
This information will be filed 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, 
incidence, severity, or outcome has not been identified in the current version of the risk analysis 
report, specified in Section 2.3. 
Details on SAE reporting is specified in Appendix 7. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
100/154 
 
 
8.3.4 
Pregnancy  
• Details of all pregnancies in participants and participant’s partners will be collected after the 
start of study intervention and until 6 months after the last administration of chemotherapy or 
3 months after last dose of xevinapant corresponding to time needed to eliminate study 
intervention(s) (e.g. 5 terminal half-lives) after the last dose of study intervention. 
• If a pregnancy is reported, the Investigator will record the pregnancy information in the CRF 
which will be reported to the Sponsor within 24 hours after awareness of the participant’s or 
partner’s pregnancy (after obtaining the necessary signed partner’s informed consent). 
• 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 /partner will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant/ 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 post study 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 
/partner, they may learn of an SAE through spontaneous reporting. 
• Any participant who becomes pregnant while participating in the study will discontinue 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. 
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 SCHNN and can be serious/life-threatening: 
• Progression 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 an SAE. These events will be recorded as part of the secondary 
endpoint. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
101/154 
 
 
• However, the event will be recorded and reported as an AE/SAE (instead of a DRE) as defined 
in Appendix 7. 
8.3.7 
Adverse Events of Special Interest  
All AESIs during the treatment period should be recorded promptly to the Sponsor and in the eCRF 
within 24 hours. Nonserious AESIs should be reported on an AESI form. In addition, serious 
AESIs must be documented on an SAE form. All SAEs must be reported as specified in 
Appendix 7. 
Based on emerging safety data collected during this and other xevinapant studies, 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 should consult the latest 
version of the Investigator’s Brochure when assessing the need to report an AESI. 
The AESIs for this study are defined below according to study period (also refer to the IB for any 
updates). 
For this study, AESI(s) include the following as listed in Section 8.3.7.1and Section 8.3.7.2. 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
102/154 
 
 
8.4 
Pharmacokinetics  
8.4.1 
Blood Sampling and Bioanalysis  
• Samples are collected only where allowed by local law/regulations. 
On all PK days (C1D2, C1D9, and C2D2; Table 4) participants take xevinapant at the hospital to 
ensure predose collection for xevinapant PK at the predose timepoint. 
Whole blood samples of approximately 3 mL per collection for measurement of plasma 
concentrations of xevinapant (including metabolite[s], such as D-1143-MET1) will be collected. 
Collection times are specified in the Pharmacokinetic Assessments SoA (Table 4). The actual date 
and time (24-hour clock time) of each sample collection will be recorded in the eCRF to calculate 
actual time elapsed since the prior dose administration. On PK days, record time of oral xevinapant 
dose, time of start and end of cisplatin infusion, and time of PK sampling for each sample in eCRF. 
In addition, record time of previous dose prior to PK sampling day (such as dose taken on C1D1, 
C1D8, C2D1) in eCRF or patient diary if taken at home. Volumes of doses taken on PK sampling 
days and prior dose needs to be recorded in eCRF (C1D1, C1D2, C1D8, C1D9, C2D1, and C2D2). 
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
103/154 
 
 
• The quantification of xevinapant in plasma will be performed using a validated bioanalytical 
method. In addition, metabolite(s) (such as D-1143-MET1) will be measured. Concentrations 
will be used to evaluate the PK of xevinapant and D-1143-MET1 via population PK approaches. 
• Remaining samples collected for analyses of xevinapant (including metabolite[s] such as 
D-1143-MET1) may also be used to evaluate safety or efficacy related to concerns arising 
during or after the study, including safety laboratory assessment and cisplatin concentrations. 
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. 
8.4.2 
PK Parameters  
The following PK parameters will be calculated, when appropriate: 
 
Symbol 
Definition 
Ctrough 
The concentration observed at the end of a dosing interval immediately before next dosing 
(xevinapant) 
• Other PK parameters might be added based on emerging data. Details will be in the IAP. 
Concentration data may be used for integrated data analyses across studies, such as population 
PK and 
, efficacy, and/or safety analyses and 
reported separately from the main CSR. 
8.5 
Genetics and/or Pharmacogenomics  
Not applicable 
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
104/154 
 
 
8.7 
Immunogenicity Assessments  
Not applicable 
8.8 
Health Economics  
Not applicable 
9 
Statistical Considerations  
Details of these analyses will be specified in the IAP. 
9.1 
Statistical Hypotheses  
No formal statistical hypothesis will be tested, as the study is designed to be exploratory. 
9.2 
Sample Size Determination  
A total of approximately 40 participants will be treated with study intervention such that 
approximately 38 DLT-like evaluable participants are anticipated to be obtained. Participants who 
prematurely discontinue, for reasons other than DLT-like events earlier than 5 weeks after start of 
treatment, may be replaced. 
The tolerability will be assessed using the DLT-like criteria (Section 8.2.5.1) during the initial 5 
weeks for each participant (DLT-like assessment period). The SMC will review the safety data. If 
the incidence of DLT-like adverse events is < 40% at the SMC review with 18 participants and the 
primary analysis, treatment will be determined to be tolerable. If the incidence of DLT-like adverse 
events is ≥ 40% at the SMC review with 18 participants and the primary analysis, SMC will make 
a recommendation based on a comprehensive assessment of all available data. In the SMC review 
with 6 and 12 participants or any in non-pre-specified SMC review, the occurrence of DLT-like 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
105/154 
 
 
events will be evaluated qualitatively, but the tolerability of the treatment will not be determined 
using the 40% threshold of DLT-like events due to the small sample size. 
The threshold of 40% is based on the previous DLT-like event rate of 33% observed in the 
xevinapant arm in Study 
 
 
 
 
 
 In general, a 
threshold of 30% is used in early oncology first in human studies; however, 40% is considered 
appropriate for this study, because the cisplatin, and IMRT based backbone treatment is known to 
already have a certain level of toxicity. 
 
 
 
The sample size is determined by having a set of DLT-like adverse event evaluable participants of 
a size, which provides an estimated incidence proportion of DLT-like adverse events below the 
threshold of 40% with a likelihood of 80%, if the true underlying incidence proportion would be 
at 30%. Based on the simulation study, the actual such probability at SMC with 18 participants is 
85.9% and actual limit of observed DLT-like events is 7 events (38.9%, CI: 17.3; 67.3). The 
following table summarize the results for entire study (i.e. probability of both SMC and PA result 
in a proportion below 40%) with varying sample size: 
Table 15 
Sample Size Calculation  
N 
Probability 
x (%) 
95% CI 
P(X ≤ x | p = 0.3) 
37 
14 (38.8) 
[17.3, 67.3] 
81.0% 
38 (selected) 
15 (39.5) 
[22.5, 57.5] 
83.0% 
39 
15 (39.5) 
[24.0, 58.8] 
82.0% 
40 
15 (38.5) 
[23.4, 57.6] 
80.6% 
N=total of DLT-like evaluable participants, x=observed DLT-like adverse events (here limit for x/N ≤ 0.4), p=true 
underlying incidence proportion for DLT-like adverse events, CI=Exact (Clopper-Pearson) confidence interval, 
P(X ≤ x | p = 0.3)=probability to observe a DLT-like adverse event incidence proportion below 40%). 
9.3 
Analysis Sets  
The analysis sets are specified below. 
Table 16 
Analysis Set  
Analysis Set 
Description 
SCR  
All participants who provided informed consent, regardless of the study intervention 
status in the study. 
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
106/154 
 
 
Analysis Set 
Description 
DLT 
All participants who were administered any dose of any study intervention and meet at 
least 1 of the following criteria: 
• 
Experienced at least one DLT like event confirmed by the SMC during the DLT 
like assessment period or for whom the composite ICE strategy led to a DLT like 
event, regardless of the administered number of doses of study 
intervention/completion in the DLT like assessment period. 
• 
Received at least 60% of the planned cumulative dose of xevinapant and cisplatin 
during the DLT-like assessment period, regardless of the completion in the DLT-
like assessment period. 
FAS/SAF 
All participants who were administered any dose of any study intervention. 
PK 
All participants, who receive at least 1 dose of xevinapant, have no relevant protocol 
deviations or important events affecting PK, and provide at least 1 measurable 
postdose concentration. 
DLT=dose-limiting toxicity, FAS=full analysis set, PK=pharmacokinetic, SAF=safety, SCR=screening. 
9.4 
Statistical Analyses  
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. 
9.4.1 
Efficacy Analyses  
All analyses on efficacy endpoints are primarily done on the FAS/SAF. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
108/154 
 
 
Reference #  
Statistical Analysis 
Laboratory results will also be classified by Grade according to NCI-CTCAE. Worst on 
treatment grades as well as shifts to worst on treatment grades will be summarized. 
Measurements without NCI-CTCAE grading will be summarized by above, within, and below 
normal limits. 
Vital parameters, weight, and ECOG performance status and corresponding changes from 
baseline will be presented as descriptive statistics by timepoint. 
Further details will be provided in the Integrated Analysis Plan. 
AE=adverse event, AESI=adverse events of special interest, CI=confidence interval, ECOG=Eastern Cooperative 
Oncology Group, MedDRA=Medical Dictionary for Regulatory Activities, NCI-CTCAE=National Cancer Institute 
Common Terminology Criteria for Adverse Events, PT=Preferred Term, SOC=System organ class, TEAE=treatment-
emergent adverse event, TRAE=treatment-related adverse event. 
9.4.3 
Other Analyses  
Details on the analyses of plasma concentrations of xevinapant (including metabolite[s], such as 
D-1143-MET1) during the treatment period will be in the IAP that will be finalized before database 
lock. 
9.4.4 
Sequence of Analyses  
The sequence of planned analyses is as shown in Table 17. 
Additional analysis during the study might be conducted, e.g. for publication or decision making 
purposes. More details will be described in the IAP and SMC Charter. 
Table 17 
Sequence of Planned Analysis  
Analysis 
SMC 
The SMC will review available data during study conduct. The cutoff for the SMC reviews will 
be triggered when 6, 12, and 18 participants have been treated for at least 5 weeks (DLT-like 
assessment period) or have experienced a DLT-like event. Additional SMC reviews may be 
requested by the Sponsor or the SMC. 
Primary analysis 
The cutoff will be triggered when at least 38 participants meet at least 1 of the following 
criteria: 
• 
Experience at least 1 DLT-like event, regardless of the administered amount of study 
intervention/completion in the DLT-like assessment period. 
• 
Receive at least 60% of the planned cumulative dose of xevinapant and cisplatin during 
the DLT-like assessment period and either complete the DLT-like assessment period or 
discontinue study. 
Follow-up 
analysis 
Follow-up analyses to report further efficacy and safety data will be done once the End of 
Study has been reached as defined in Section 4.4. 
DLT=dose-limiting toxicity, SMC=Safety Monitoring Committee. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
109/154 
 
 
10 
References  
Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation 
therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable 
squamous cell head and neck cancer. J Clin Oncol. 2003;21(1):92-8.  
Bauml JM, Vinnakota R, Anna Park YH, et al. Cisplatin Every 3 Weeks Versus Weekly With 
Definitive Concurrent Radiotherapy for Squamous Cell Carcinoma of the Head and Neck. J Natl 
Cancer Inst. 2019; 1;111(5):490-7.  
Becker PS, Griffiths EA, Alwan LM, et al. NCCN Guidelines Insights: Hematopoietic Growth 
Factors, Version 1.2020. J Natl Compr Canc Netw.2020;18(1):12-22.  
Biau J, Lapeyre M, Troussier I, et al. Selection of lymph node target volumes for definitive head 
and neck radiation therapy: a 2019 Update. Radiother Oncol. 2019;134:1-9.  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (Version 1.1). Eur J Cancer. 2009;45:228-47.  
Elad S. The MASCC/ISOO Mucositis Guidelines 2019 Update: introduction to the first set of 
articles. Support Care Cancer. 2019;27:3929-31.  
Espeli V, Zucca E, Ghielmini M, et al. Weekly and 3-weekly cisplatin concurrent with intensity-
modulated radiotherapy in locally advanced head and neck squamous cell cancer. Oral Oncol. 
2012; 48:266-71.  
Ferlay J, Colombet M, Soerjomataram I, et al. Cancer statistics for the year 2020: An overview. 
Int J Cancer. 2021;149:778-9.  
Ghosh-Laskar S, Yathiraj PH, Dutta D, et al. Prospective randomized controlled trial to compare 
3-dimensional conformal radiotherapy to intensity-modulated radiotherapy in head and neck 
squamous cell carcinoma: Long-term results. Head Neck. 2016;38 Suppl 1:E1481-7.  
Gregoire V, Lefebvre JL, Licitra L, et al. EHNS-ESMO-ESTRO Guidelines Working Group. 
Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v184-6.  
Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with 
anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 
2003;362:1255-60.  
Hernandez-Vila C. Current prognosis and quality of life following surgical treatment for head and 
neck squamous cell carcinoma. Plast Aesthet Res. 2016;3:203-10.  
Jellema AP, Slotman BJ, Doornaert P, et al. Impact of radiation-induced xerostomia on quality of 
life after primary radiotherapy among patients with head and neck cancer. Int J Radiat Oncol Biol 
Phys. 2007;69:751-60.  
Lambin P, Ramaekers BLT, van Mastrigt GAPG, et al. Erythropoietin as an adjuvant treatment 
with (chemo) radiation therapy for head and neck cancer. Cochrane Database Syst Rev. 
2009;3:CD006158:1-27.  
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
110/154 
 
 
Machiels J-P, Leemans CR, Golusinski W, et al. Squamous cell carcinoma of the oral cavity, 
larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Anns of Oncology. 2020;31(11):1462-75.  
Marta GN, Saad ED. Assessment of quality of life in phase III trials of radiotherapy in localized 
or locally advanced head and neck cancer over the past 17 years. Ann Palliat Med. 2017;6(1):73-
80.  
Matzinger O, Viertl D, Tsoutsou P, et al, The radiosensitizing activity of the SMAC-mimetic, 
Debio 1143, is TNFα-mediated in head and neck squamous cell carcinoma. Radiother Oncol. 
2015;116(3):4.Epub.  
National Comprehensive Cancer Network, NCCN chemotherapy order templates (NCCN 
templates) appendix B, 2020.  
Nicholson DW. From bench to clinic with apoptosis-based therapeutic agents. Nature 
2000;407(6805):810-6.  
Oun R, Moussa YE, Wheate NJ. The side effects of platinum-based chemotherapy drugs: a review 
for chemists. Dalton Trans. 2018;47:6645-53.  
Peterson DE, Boers-Doets CB, Bensadoun RJ, et al. ESMO Guidelines Committee. Management 
of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, 
treatment, and follow-up. Ann Oncol. 2015;26:(S5):v139-51.  
 
  
Porceddu SV, Scotte F, Aapro M, et al. Treating patients with locally advanced squamous cell 
carcinoma of the head and neck unsuitable to receive cisplatin-based therapy. Front Oncol. 
2020;9:Epub.  
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.  
Roila F, Molassiotis A, Herrstedt J, et al. MASCC and ESMO guideline update for the prevention 
of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in 
advanced cancer patients. Ann Oncol. 2016 27;(5):v119-33.  
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, Tijeras-Raballand A, 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. 
AACR Annual Meeting. Cancer Res. 1 2014; 74 (19_Supplement):2752.  
Sharma A, Kumar M, Bhasker S, et al. An open-label, noninferiority phase III RCT of weekly 
versus three weekly cisplatin and radical radiotherapy in locally advanced head and neck squamous 
cell carcinoma (ConCERT trial). J Clin Oncol. 2022 40:16_suppl, 6004  
Strojan P, Corry J, Eisbruch A, et al. Recurrent and second primary squamous cell carcinoma of 
the head and neck: When and how to reirradiate. Head Neck. 2015;37:134-50.  
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
111/154 
 
 
 
 
  
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.  
Sung H, Ferlay J, Siegel RL, et al.Global cancer statistics 2020: GLOBOCAN estimates of 
incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer. J Clin 2021 0;1-
41.  
Szturz P, Wouters K, Kiyota N, et al. Weekly Low-Dose Versus Three-Weekly High-Dose 
Cisplatin for Concurrent Chemoradiation in Locoregionally Advanced Non-Nasopharyngeal Head 
and Neck Cancer: A Systematic Review and Meta-Analysis of Aggregate Data. Oncologist. 
2017;22(9):1056-66.  
Szturz P, Wouters K, Kiyota N, et al. Low-Dose vs. High-Dose Cisplatin: Lessons Learned From 
59 Chemoradiotherapy Trials in Head and Neck Cancer. Front Oncol. 2019 21;9:86.  
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):1113-24  
Tao Y, Sun XS, Pointreau Y, et al. Extended follow-up of a phase 2 trial of xevinapant plus 
chemoradiotherapy in high-risk locally advanced squamous cell carcinoma of the head and neck: 
a randomised clinical trial. Eur Journal of Oncology. 2023; 5(183):24-37.  
WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain in 
adults and adolescents 2018.  
Wilkins AC, Rosenfelder N, Schick U, et al. Equivalence of cisplatin and carboplatin-based 
chemoradiation for locally advanced squamous cell carcinoma of the head and neck: a matched-
pair analysis. Oral Oncol. 2013; 49(6):615-9.  
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
112/154 
 
 
11 
Appendices  
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
113/154 
 
 
Appendix 1 
Abbreviations  
 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse events of special interest 
AJCC 
American Joint Committee on Cancer 
AxMP 
auxiliary medicinal product 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BOR 
best overall response 
CDMO 
Contract Development Manufacturing Organization 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COVID-19 
Corona virus disease-19 
CR 
complete response 
CrCL 
creatine clearance 
CRF 
case report form 
CRO 
clinical research organization 
CRR 
complete response rate 
CRT 
chemoradiotherapy 
CSR 
clinical study report 
CT 
clinical trials, computed tomography 
CTA 
clinical trial application 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDI 
drug-drug interactions 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DRE 
disease-related events 
EAC 
Endpoint Adjudication Committee 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
114/154 
 
 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
END 
elective neck dissection 
EOT 
end of treatment 
ESMO 
European Society for Medical Oncology 
ER 
emergency room 
18F-FDG 
¹⁸F-Fluorodeoxyglucose 
FAS 
full analysis set 
FFPE 
formalin-fixed paraffin-embedded 
FU 
follow-up 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factors 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
hCG 
human Chorionic Gonadotropin 
HCP 
healthcare provider 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPV 
human papillomavirus 
IAP 
integrated analysis plan or inhibitor of apoptosis proteins 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
Independent data monitoring committee 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product  
IMRT 
intensity-modulated radiation therapy 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
115/154 
 
 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRT 
interactive response technology 
IVDR 
In Vitro Diagnostic Medical Device Regulation 
LA SCCHN locally advanced squamous cell carcinoma of the head and neck 
LRC 
locoregional control 
MASCC 
Multinational Association of Supportive Care in Cancer 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI-
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events  
NIMP 
noninvestigational medicinal product 
OPC 
oropharyngeal cancer 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic, progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
permeability glycoprotein 
PK 
Pharmacokinetic 
POCBP 
Person of Childbearing Potential 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
PTV 
planning target volume 
QTcF 
corrected QT interval by Fridericia’ formula 
QTL 
quality tolerance limit 
QW 
Weekly 
Q3W 
every 3 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumor 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
116/154 
 
 
RT 
Radiotherapy 
RT-QA 
RadioTherapy Quality Assurance 
SAE 
serious adverse event 
SAF 
Safety 
SCCHN 
squamous cell carcinoma of the head and neck 
SCR 
Screening 
SDV 
source data verification 
SMC 
Safety Monitoring Committee 
SoA 
schedule of activities 
SoC 
standard of care 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TRAE 
treatment-related adverse event 
ULN 
upper limit of normal 
 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
117/154 
 
 
Appendix 2 
Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 
Applied to This Study in Locally Advanced SCCHN  
The text below was derived from Eisenhauer 2009 and Schwartz 2016. Guidance, adjustments and 
clarification specific to this study in locally advanced SCCHN, and not necessarily in the original 
articles, has been added. 
Background and Definitions 
Response and progression will be evaluated in this study based on the international criteria 
proposed by the RECIST Working Group (Version 1.1). Unidimensional measurements of tumor 
lesions are used in the RECIST criteria. Individual lesions are either measurable or non-measurable 
using the criteria provided below. 
Study-permitted Imaging Modalities and Associated Procedures  
• CT, MRI 
CT is the best and most reproducible method currently available to measure lesions selected for 
response assessment. If CT scans have a slice thickness greater than 5 mm, the minimum size for 
a measurable lesion should be twice the slice thickness. MRI is also acceptable in this study, except 
for chest imaging, where CT is mandatory. 
• Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Needle localization images for biopsy site may however be useful. 
• Endoscopy, laparoscopy 
The utilization of these techniques alone for objective tumor evaluation is not permitted in this 
study. In this study, biopsy (endoscopic or otherwise) of a suspected new lesion to confirm or 
exclude malignant nature and provide relevant histological information is strongly encouraged 
when clinically feasible. Unbiopsied apparent recurrences visible only on endoscopy are not 
considered sufficient evidence alone to be markers of progression. 
• Tumor markers 
Tumor markers for progression are not used in this study. 
• Cytology, histology 
In this study, biopsy of a suspected new lesion or residual/recurrent mass to confirm or exclude 
malignant nature and provide histological information relevant to the endpoint is strongly 
encouraged when clinically feasible. 
• 18F-FDG -PET + CT 
This study incorporates 18F-FDG -PET scanning to complement CT/MRI scans in assessment of 
progression (particularly possible ‘new’ disease.) However, the use of 18F-FDG-PET to upgrade 
response to CR unsupported by biopsy is not applied to this study. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
118/154 
 
 
Assessment Methodology 
• Assessment methodology of measurable lesions selected for measurement 
Non-nodal tumor lesions must be accurately measured in 1 dimension, the longest diameter in the 
plane of measurement, with a minimum size of 10 mm by CT scan (irrespective of scanner type) 
and MRI (no less than double the slice thickness and a minimum of 10 mm). Clinical observations, 
clinical caliper measurements, photographic assessments, and plain radiographs are not permitted 
in this study. All measurements should be recorded in metric notation. 
The short axis of a lymph node, or conjoined mass of nodes, is the longest perpendicular to the 
longest diameter in the axial plane. To be considered pathologically enlarged and measurable at 
baseline, a lymph node must be ≥ 15 mm in short axis when assessed by CT or MRI scan (Scan 
slice thickness recommended to be no greater than 5 mm). At Baseline and in follow-up, only the 
short axis of nodes will be measured and followed. 
• Assessment methodology of nonmeasurable disease 
All other lesions (or sites of disease), including small lesions (< 10 mm using spiral CT or MRI 
scan), as well as measurable lesions that are not selected as target lesions, are considered non-target 
disease. RECIST criteria define many baseline types of lesion that are always non-measurable, but 
all of these are excluded from this study. Participants with only non-measurable disease at baseline 
but whose overall disease burden is still assessable by imaging are considered to have evaluable 
(non-measurable) disease. 
• Assessment of special lesion types 
a) Bone lesions. There will be no malignant bone lesions at baseline in this study due to 
inclusion/exclusion criteria, hence discussion of measurability of bone lesions at baseline 
and of lesions seen at baseline on bone scans is unnecessary. 
b) Cystic lesions. Radiographically defined simple cysts should not be considered as 
malignant lesions. Complex malignant cystic lesions will not occur at baseline in this study 
due to inclusion/exclusion criteria and hence need not be considered further. 
c) Lesions with local irradiation: In this study, all lesions seen at baseline will receive 
irradiation as part of the study treatment, and therefore it is impossible to avoid radiation 
impact on assessments. As a result, the processes of selection and following of target 
lesions should not be influenced by past or current irradiation.
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
119/154 
 
 
Process for Evaluation of Disease at Baseline 
All baseline evaluations except 18F-FDG-PET scan should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 18F-FDG-PET 
scan performed within 4 weeks before ICF signature could be used at baseline evaluation. The 
same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. 
• Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but also should be those suitable for reproducible repeated measurements. 
Lymph nodes: Pathological nodes which are defined as measurable and may be identified as target 
lesions at baseline must have a short axis of ≥ 15 mm by CT or MRI scan. Only the short axis of 
these nodes will contribute to the baseline sum of diameters. All other pathological nodes (those 
with short axis ≥ 10 mm but < 15 mm) should be considered nontarget lesions. Nodes that have a 
short axis < 10 mm at baseline are considered nonpathological and should not be recorded or 
followed. 
A sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and recorded as the baseline sum of diameters. The baseline sum of diameters 
will be used as reference to further characterize any later objective tumor changes in the 
measurable dimension of the disease. 
• Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget lesions. Measurements are not required, except short axis of nodes and then only to 
confirm or exclude pathological enlargement: these lesions should be subsequently assess all 
together as complete response, noncomplete response, or progressive disease. Progressive disease 
has to be unequivocal, and based on the entire nontarget lesion burden, unless there is only 
1 nontarget lesion. Multiple nontarget lesions involving the same organ can be a single item on the 
case record form (e.g. ‘multiple liver metastases’). 
Process for Assessment of Disease at Each Timepoint After Baseline 
• Evaluation of Target Lesions 
A new sum of diameters for all target lesions will be calculated and recorded as the sum of 
diameters for that timepoint. This timepoint sum of diameters will be used for comparison with 
that at baseline and at the timepoint when the sum of diameters is least (the nadir): the details of 
the outcome of each comparison are shown in Table 18 below. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
123/154 
 
 
CR=complete response, NE=not evaluable, PD=progressive disease. 
• Special points 
Impact of biopsy and excision. Due to biopsy or excision of target lesions, some participants with 
measurable disease at baseline may have a timepoint response or best overall response of Non-
CR/Non-PD 
Symptomatic progression. Symptomatic progression alone is not a determinant of disease 
progression in this study. 
Handling equivocal findings of progression. For equivocal findings of progression (e.g. very small 
and uncertain new lesions; cystic changes or necrosis in existing lesions), in the absence of 
histological verification of new malignant lesions, treatment may continue at the investigator’s 
discretion until the next scheduled assessment. If, at the next scheduled assessment, progression is 
definite, the date of progression should be the earlier date when progression was first suspected 
Further Information 
Further information on the assessment of disease by imaging in this study is available in the 
training materials, including slide presentations and/ or videos. 
 
 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
124/154 
 
 
Appendix 3 
Cisplatin Administration  
Please Consult and Follow the Instructions Provided in Your Local Label. 
Preparation 
Do not use needles or intravenous sets containing aluminum parts that can come in contact with 
cisplatin for injection during preparation or administration. Aluminum reacts with cisplatin for 
injection, causing precipitate formation, and a loss of potency. 
Cisplatin for injection is a cytotoxic drug. Follow applicable special handling and disposable 
procedures. 
Dilution 
For preparation of the infusion solution, it is recommended that the solution be further diluted in 
1 to 2 L of a compatible infusion solution with or without 37.5 g of mannitol. Refer to detailed 
references for specific infusion solution stability and compatibility information. 
Administration 
Administer cisplatin for injection by slow intravenous infusion. 
Warnings and Precautions 
Nephrotoxicity 
Cisplatin for injection can cause dose-related nephrotoxicity, including acute renal failure that 
becomes more prolonged and severe with repeated courses of the drug. Renal toxicity typically 
begins during the second week after a dose of cisplatin for injection. Patients with baseline renal 
impairment, geriatric patients, patients who are taking other nephrotoxic drugs, or patients who 
are not well hydrated may be more susceptible to nephrotoxicity. 
Ensure adequate hydration before, during, and after cisplatin for injection administration (see 
Appendix 4). Measure serum creatinine, blood urea nitrogen, creatinine clearance, and serum 
electrolytes including magnesium prior to initiating therapy, and as clinically indicated. Consider 
magnesium supplementation as clinically needed. 
 
 
 
Peripheral Neuropathy 
Cisplatin for injection can cause dose-related peripheral neuropathy that becomes more severe with 
repeated courses of the drug. Neurologic symptoms have been reported to occur after a single dose. 
Neuropathy can also have a delayed onset from 3 to 8 weeks after the last dose of cisplatin for 
injection. Manifestations include paresthesias in a stocking-glove distribution, areflexia, and loss 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
125/154 
 
 
of proprioception and vibratory sensation. The neuropathy may progress further even after 
stopping treatment. Peripheral neuropathy may be irreversible in some patients. 
Consider permanent discontinuation of cisplatin for injection for participants who develop 
symptomatic peripheral neuropathy. Geriatric patients may be more susceptible to peripheral 
neuropathy. 
Nausea and Vomiting 
Cisplatin for injection is a highly emetogenic antineoplastic agent. Premedicate with antiemetic 
agents. Without antiemetic therapy, marked nausea and vomiting occur in almost all patients 
treated with cisplatin for injection and may be so severe that the drug must be discontinued. Nausea 
and vomiting may begin within 1 to 4 hours after treatment and last up to 72 hours. Maximal 
intensity occurs 48 to 72 hours after administration. Various degrees of vomiting, nausea, and/or 
anorexia may persist for up to 1 week after treatment. Delayed nausea and vomiting (begins or 
persists 24 hours or more after chemotherapy) has occurred in patients attaining complete emetic 
control on the day of cisplatin for injection therapy. Consider the use of additional antiemetics 
following infusion. 
Myelosuppression 
Myelosuppression suppression occurs in 25% to 30% of patients treated with cisplatin for 
injection. Fever and infection have been reported in patients with neutropenia. Potential fatalities 
due to infection (secondary to myelosuppression) have been reported. Geriatric patients may be 
more susceptible to myelosuppression. 
Perform standard hematologic tests before initiating cisplatin for injection, before each subsequent 
course, and as clinically indicated. Closely monitor participants for the development of signs and 
symptoms of infection during and after treatment with cisplatin for injection. For participants who 
develop severe myelosuppression during treatment with cisplatin for injection, consider dose 
modifications, and manage according to clinical treatment guidelines. 
Hypersensitivity Reactions 
Cisplatin for injection can cause severe hypersensitivity reactions, including anaphylaxis, and 
death. Manifestations have included facial edema, wheezing, tachycardia, and hypotension. 
Hypersensitivity reactions have occurred within minutes of administration to patients with prior 
exposure to cisplatin for injection. 
Monitor participants receiving cisplatin for injection for possible hypersensitivity reactions. 
Ensure supportive equipment and medications are available to treat severe hypersensitivity 
reactions. Severe hypersensitivity reactions require immediate discontinuation of cisplatin for 
injection and aggressive therapy. Participants with a history of severe hypersensitivity reactions 
should not be rechallenged with cisplatin for injection. Cross-reactivity between platinum-based 
antineoplastic agents has been reported. Cases of severe hypersensitivity reactions have recurred 
after rechallenging patients with a different platinum agent. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
126/154 
 
 
Ototoxicity 
Cisplatin for injection can cause ototoxicity, which is cumulative, and may be severe. Consider 
audiometric and vestibular function monitoring. 
Ototoxicity is manifested by tinnitus, hearing loss in the high-frequency range (4,000 to 8,000 Hz) 
and/or decreased ability to hear normal conversational tones. Ototoxicity can occur during or after 
treatment and can be unilateral or bilateral. Deafness after the initial dose of cisplatin for injection 
has been reported. Vestibular toxicity has also been reported. 
Ototoxic effects can be more severe and detrimental in pediatric patients, particularly in patients 
less than 5 years of age. The prevalence of hearing loss in pediatric patients is estimated to be 
40-60%. Additional risk factors for ototoxicity include simultaneous cranial irradiation, treatment 
with other ototoxic drugs and renal impairment. Consider audiometric and vestibular testing in all 
pediatric patients receiving cisplatin. 
Genetic factors (e.g. variants in the thiopurine S-methyltransferase [TPMT] gene) may also 
contribute to the cisplatin-induced ototoxicity, although this association has not been consistent 
across populations and study designs. 
Ocular Toxicity 
Optic neuritis, papilledema, and cortical blindness have been reported in patients receiving 
standard recommended doses of cisplatin for injection. Blurred vision and altered color perception 
have been reported after the use of regimens with higher doses and dose frequencies of cisplatin 
for injection. The altered color perception manifests as a loss of color discrimination, particularly 
in the blue-yellow axis and irregular retinal pigmentation of the macular area on fundoscopic exam. 
Improvement and/or total recovery usually occurs after discontinuing cisplatin for injection but 
can be delayed. 
Secondary Malignancies 
The development of acute leukemia secondary to the use of cisplatin for injection has been 
reported. In these reports, cisplatin for injection was generally given in combination with other 
leukemogenic agents. 
Embryo-fetal Toxicity 
Based on human data, cisplatin for injection can cause fetal harm when administered to a pregnant 
woman. Advise pregnant women and females of reproductive potential of the potential risk to a 
fetus. Advise females of reproductive potential to use effective contraception during treatment and 
for 6 months or according to local guidelines and/or local product information (whichever is 
longest) after the last dose of cisplatin for injection. Advise male participants with female partners 
of reproductive potential to use effective contraception during treatment and for 6 months or 
according to local guidelines and/or local product information (whichever is longest) after the last 
dose of cisplatin for injection. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
127/154 
 
 
Injection Site Reactions 
Injection site reactions can occur during the administration of cisplatin for injection. Local soft 
tissue toxicity has been reported following extravasation of cisplatin for injection. Severity of the 
local tissue toxicity appears to be related to the concentration of the cisplatin for injection solution. 
Infusion of solutions with a cisplatin for injection concentration greater than 0.5 mg/mL may result 
in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema. 
Because of the possibility of extravasation, closely monitor the infusion site during drug 
administration. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
128/154 
 
 
Appendix 4 
Cisplatin Hydration Guidelines  
Adequate hydration must be maintained from 2 to 3 hours prior to administration until minimum 
of 2 hours after the administration of cisplatin (SmPC TEVA v6.0 2019). 
Hydration is necessary to cause sufficient diuresis during and after treatment with cisplatin. It is 
realized by intravenous infusion of one of the following solutions: 
• Sodium chloride solution 0.9% 
• Mixture of sodium chloride solution 0.9% and glucose solution 5% (1:1). 
Hydration prior to treatment with cisplatin: 
• Intravenous infusion for a period of 2 to 3 hours, with a total amount of at least 1 L. 
Hydration after termination of the administration of cisplatin: 
• Intravenous infusion of another 2 liters for a period of at least 2 hours. 
• Additional hydration on days 2 and 3 post-cisplatin dosing as per institutional guidelines. 
Efforts to maintain urine output to 100 mL/hour on the day of cisplatin administration is important 
and forced diuresis should be required as appropriate, by taking the increase or decrease in in-out 
balance and body weight into account. Forced diuresis may be realized by intravenously 
administering 37.5 g mannitol as a 10% solution (375 mL mannitol solution 10%), or by 
administration of a diuretic if the kidney functions are normal. The administration of mannitol or 
a diuretic is also required when the administrated cisplatin dose is higher than 60 mg/m2 of body 
surface. 
It is necessary that the participant drinks large quantities of liquids for 24 hours after the cisplatin 
infusion to ensure adequate urine secretion. 
Hydration guidelines may be modified at the discretion of the treating physician provided adequate 
pre and postcisplatin hydration is achieved, and renal function remains adequate. 
Consider a More Extensive Hydration Regimen Under Certain Circumstances: 
Additional pre-hydration with normal saline iv or orally at minimum in the 48 hours preceding 
cisplatin infusion and a more extensive posthydration regimen (recommended 1,000-1,500 mL on 
days 2 to 3 post-cisplatin dose) is requested whenever possible in those participants with risk 
factors for renal toxicity, e.g. proteinuria, diabetes, and hypertension. 
 
 
 Attention should also by paid to any signs of dehydration (insufficient urine 
outputs) or conditions leading to a potential dehydration like diarrhea, vomiting, undernutrition, 
infection/fever. 
 
 
 
 
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
129/154 
 
 
Appendix 5 
Study Governance  
Financial Disclosure 
Investigators and Subinvestigators 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 their representative will explain the nature of the studyincluding the risks, 
and benefits, to the participant, and answer all questions on the study. 
• Participants will be informed that their participation is voluntary. 
• Participants will be required to sign a statement of informed consent that meets the requirements 
of 21 CFR 50; local regulations; ICH guidelines; privacy and data protection 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 reconsented 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 their 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. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
130/154 
 
 
• 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 the US, Europe, 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, RT-QA review center, and CDMO. 
• Drug supply and distribution are handled via CDMO including regional depots. 
Details of structures and associated procedures will be defined separately in an Integrated Study 
Management Plan and the associated functional study plans. 
Safety Monitoring Committee 
An SMC will be formed in this study before the start of study intervention of the first participant 
and will assess the tolerability and safety during the study (See Section 8.2.5 and 9.2 for details). 
The SMC consists of Sponsor representatives (including, but not limited to the Medical 
Responsible, the Patient Safety Strategy Lead, and the Biostatistician), the coordinating 
Investigator, and external experts, if applicable. The full membership, mandate, and processes of 
the SMC will be detailed in the SMC charter. 
RT-QA Review Center 
1 or more RT-QA Review Centers will be identified. The responsibilities of the RT-QA Review 
Center can include: 
• Reviewing and provide suggestions to IMRT plan(s) before starting the first fraction 
administration to ensure IMRT requirements compliance. 
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. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and the following: 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
131/154 
 
 
o Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and CIOMS International Ethical Guidelines 
o Applicable ICH GCP Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments (if applicable), ICF, IB, and other relevant documents (e.g. 
advertisements) will be submitted to an IRB/IEC for review and approval before the study is 
initiated. 
• 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 their 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. 
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. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
132/154 
 
 
Clinical Study Insurance and Compensation to Participants 
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, 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 will be reported in a 
CSR addendum, if applicable. 
• Posting of data on ClinicalTrials.gov, the Clinical Trial Information System (CTIS), 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 
• All participant study data will be recorded on printed or electronic CRFs 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 CRF. Details for managing CRFs are in the Data Management Plan. 
• The Investigator will maintain accurate documentation (source data) that supports the 
information in the CRF. 
• 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. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
133/154 
 
 
• QTLs will be predefined and documented in the Risk-based Monitoring and Operations 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, including definition of study critical data items and 
processes (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 Clinical Operating 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 CRF 
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, and all applicable regulatory requirements. 
• The Investigator will retain records and documents, including signed ICFs, pertaining to the 
conduct of this study for the required length of time after study completion, per all applicable 
regulations, institutional policies, or contractual agreement. 
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 CRFs. 
• Data recorded on CRFs 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 
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 ensures 
that no destruction of medical records is performed without the Sponsor’s written approval. 
• Definition of what constitutes source data, and its origin is found in Clinical Operating Plan. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
134/154 
 
 
Study and Site Start and Closure 
The study start date is when the first participant signs the Informed Consent Form. 
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. 
The Sponsor will decide which study procedures/assessments that are not related to participant 
safety will be discontinued. 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. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
135/154 
 
 
Appendix 6 
Contraception and Barrier Requirements  
Definitions: 
POCBP: 
A participant 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 xevinapant, 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 participant 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 participant on HRT and whose menopausal status are in doubt will be required to use 1 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. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
136/154 
 
 
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 
POCBP 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 xevinapant. 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) 
• 
External or internal 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. 
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 (external or internal 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, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM are not acceptable methods of contraception for this study. External and internal 
condoms cannot be used together (due to risk of failure from friction). 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
137/154 
 
 
Appendix 7 
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 (e.g. 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 per the Investigator’s medical and scientific judgment, are considered 
clinically significant in the medical and scientific judgment of the Investigator (e.g. not 
related to progression of underlying disease, but may be leading to study intervention 
discontinuation). 
• 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 SAE. However, the signs, symptoms, and/or clinical sequelae resulting from lack 
of efficacy will be reported as an AE or 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. 
• Medical or surgical procedure (e.g. endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
143/154 
 
 
• The paper form will be transmitted to the Sponsor or its designee within 24 hours by email 
or facsimile (fax to mail). 
• 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 paper form within 24 hours after becoming aware of the event. 
• Additional documents (e.g. laboratory reports, autopsy report, and hospital discharge letter) 
may be required in addition. 
Recording and Reporting of DLTs 
• Each event that meets the DLT criteria, as specified in Section 8.2.5.1, will be recorded in 
the CRF within 24 hours after awareness of the event. 
• Serious DLTs will be reported in an expedited manner, using the SAE reporting process, as 
specified above. 
• Notification of each DLT related event (nonserious and serious) will be reported to the 
Sponsor or its designee within 24 hours from the date of awareness. 
Reporting of AESIs 
• Serious and nonserious AESIs will be recorded by the site within 24 hours in the CRF, 
using the same process as stated in the section above “Reporting of SAEs”. 
• Paper report forms may be used as a back-up method for an EDC system failure and will be 
transmitted to the Sponsor or its designee within 24 hours by facsimile (fax to mail) or email. 
Reporting of Pregnancies 
• Pregnancy and abnormal pregnancy outcomes (participant/partner/child/fetus) will be 
recorded in the CRF and submitted to the Sponsor within 24 hours. Specific guidance is 
provided in the CRF Completion Guideline. 
• Paper report forms may be used as a back-up method for an EDC system failure and will be 
transmitted to the Sponsor or its designee within 24 hours by facsimile (fax to mail) or email. 
 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
144/154 
 
 
Appendix 8 
Clinical Laboratory Tests  
The protocol-required clinical laboratory assessments are in the following table: 
 
Laboratory 
Assessment 
Parameters 
Biochemistry1 
(full panel) 
Albumin 
Glomerular Filtration Rate, Calculatedd 
Alanine Aminotransferasea 
Glucose 
Alkaline Phosphataseb 
Lipase 
Amylase 
Potassium 
Aspartate Aminotransferasea 
Sodium 
Total Bilirubin 
Protein 
Direct Bilirubinc 
Blood urea nitrogen/urea 
Calcium 
C-reactive protein 
Creatinine 
Uric acid 
 
Magnesium 
Biochemistry1 
(minimum panel) 
Alanine Aminotransferasea 
Lipase 
Alkaline Phosphataseb 
Potassium 
Amylase 
Sodium 
Aspartate Aminotransferasea 
Blood urea nitrogen/urea 
Total Bilirubin 
Magnesium 
Direct Bilirubin 
 
Creatinine 
 
a 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. 
b If alkaline phosphatase is elevated, consider measuring the alkaline phosphatase isoenzymes 
c Only If total Bilirubin > ULN 
 
 
Hematology 
Hematocrit 
Platelets 
Hemoglobin 
Mean corpuscular volume (MCV) 
Leukocytes with Differential: 
Neutrophils (absolute/%) 
Lymphocytes (absolute/%) 
Monocytes (absolute/%) 
Eosinophils (absolute/%) 
Basophils(absolute/%) 
Mean corpuscular hemoglobin (MCH) 
Erythrocytes (RBC) 
Coagulation 
Prothrombin Intl. Normalized Ratio, if applicable (e.g. under oral anticoagulation medication) 
Activated partial thromboplastin time 
Fibrinogen 
Routine 
Urinalysis 
Specific gravity, pH, glucose, protein, blood, ketones, leukocytes by dipstick. 
Microscopic examination (if blood or protein is abnormal). 
 
Contraception 
and Pregnancy 
Follicle Stimulating Hormone (for females, as needed, if not POCBP) 
Serum or highly sensitive urine] hCG pregnancy test (as needed for a POCBP). Serum hCG 
pregnancy test during screening, local urine test thereafter [Note: urine testing at a local 
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
145/154 
 
 
Laboratory 
Assessment 
Parameters 
laboratory will be standard for the protocol. If required by local regulations or the IRB/IEC, 
serum testing will be done instead].  
Serology 
HBsAg and HBcAb 
HPV status by p16 IHC 
HCV-antibody and HCV-RNA by PCR 
SARS-CoV-2 (RNA by PCR and/or antigen test) 
(see Section 5.2 when test is applicable) 
HIV 1/2 antibodies 
 
HBcAb=Hepatitis B core antibody, HBsAg=Hepatitis B surface antigen, hCG=human Chorionic Gonadotropin, 
HCV=Hepatitis C Virus, HIV=human immunodeficiency virus, HPV=Human papillomavirus, IEC=Independent Ethics 
Committee, IHC=immunohistochemistry, IRB=Institutional Review Board, MCH=Mean corpuscular hemoglobin, 
MCV=Mean corpuscular volume, PCR=polymerase chain reaction, POCBP=Person of Childbearing Potential, 
RBC=red blood cell, SARS-CoV-2=Severe acute respiratory syndrome coronavirus 2, ULN=upper limit of normal. 
All study-required laboratory assessments will be performed by a local laboratory. For HPV 
testing, see Section 8.2.4. 
 
 
 
CCI
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
146/154 
 
 
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. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
147/154 
 
 
Appendix 10 
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. 
CCI
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
148/154 
 
 
Recommendations for Mitigation Measures During the COVID-19 Pandemic 
Considerations for participants’ eligibility 
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 #6 “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 different 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. 
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. 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
149/154 
 
 
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 7 and 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. 
 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
150/154 
 
 
Appendix 11 
Country-specific Requirements  
Not applicable 
 
 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
151/154 
 
 
Appendix 12 
Protocol Amendment History  
The information for the current amendment is on the title page. 
 
 
CCI

Xevinapant 
Phase 1b Xevinapant and QW Cisplatin RT in Unresected LA SCHNN 
MS202359_0025 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
154/154 
 
 
Appendix 15 
Principal Investigator Signature Page  
 
Study Title: 
A Single Arm, Open label, Phase 1b Study of Xevinapant 
in Combination With Weekly Cisplatin and Intensity-
modulated Radiotherapy to Assess Safety and Tolerability 
in Participants with Locally Advanced Squamous Cell 
Carcinoma of the Head and Neck, Suitable for Definitive 
Chemoradiotherapy 
Regulatory Agency Identifying 
Numbers: 
IND:14330 
EU trial number: 2023-505796-76-00 
Clinical Study Protocol Version: 
27 November 2023/Version 2.0 
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: 
 
 
CCI